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Full text of "Harvard medical alumni bulletin"

AUTUMN 2006 




i 



ALUMNI BULLETIN 



SPARKS OF 
INSPIRATION, 

i^hysicians anc. 
scientists reflect 
on some of the 
defining moments— 
the sudden insights. 



IIIIifliIiliKUIRIB[tKIS[QiSl 



or the challenges to 
accepted wisdom— 
that have ignitec. 
their innovations 
in medicine. 



AUTUMN 2006 • VOLUME 80, NUMBER 2 



CONTENTS 



DEPARTMENTS 



Letters 3 

Pulse 6 

The School welcomes its newest class as 
it celebrates the centennial of its longest- 
hved home; the dean takes stock as he 
announces plans to step down 

g President's Report 9 

i byAWKarchmer 

° Curbside Consultation 10 

I Lessons from the Holocaust in how 
> doctors can heal through hope 
i by Harold]. Bursztajn 

I Bookmark 12 

g A review by Elissa Ely of The Mind Has 
I Mountains: Reflections on Society and Psychiatry 

I Bookshelf 13 

i Benchmarks 14 

5 The migraines that signal potential 

i heart trouble for women; children's 

I health considered; the health effects of 

I red wine and red meat 

r 

I Class Notes 58 

o 

I Obituaries 61 

g Endnotes 64 

^ The pressures of a pathology exam 
5 inspire medical students to turn 
\ pathological in their humor. 

o 
o 

E Cover photograph: Chris Collins/Veer 






SPECIAL REPORT: SPARKS OF INSPIRATION 



Introduction 18 

articles by ANN marie menting and pat mccaffrey 

Eye of the Storm 20 

Ernest Darkoh defies the skeptics and 
helps a nation save itself. 

_ , SigndCorps 24 

:~»^ Joan Brugge chips away at the secrets of 
a disease that claimed her sister. 

^^ The Thin Red Line 28 

Judah Folkman devotes decades to proving 
an unpopular theory. 

The Possible Dream 32 

|p>HM ? Jim Yong Kim advocates for change in 
the moral debate over treatment. 

^^ ^ Second Sight 36 

Carta Shatz rewrites some of science's 
most sacred scriptures. 

^ Collateral Damage 40 

Kilmer McCully connects the dots in 
cases separated by decades. 

"^™ No Child Left Behind 44 

Catherine Wilfert turns her 

lijk^- "^Mki gaze to the smallest victims of HIV. 



FEATURES 



Pilgrim's Progress. 



A physician travels to a medical mecca in search of a 

sense of control over the outcome of his own cancer surgery. 

b^-RAY BABINEAU 

Animal Rites 

Some patients are wilder than others, b}- Stanley perkins 



48 



52 



m 



H;^rv;^rrl MpHip^I 





in This Issue 

HIS ISSUE OF THE BULLETIN IS, IN ITS WAY, A MEDITATION ON THE 

relationship of hedgehog and fox in medicine. "The fox knows many 
things, but the hedgehog knows one big thing," wrote Archilochos 
26 centuries ago. A mercenary soldier and an angry man, he was also a poet, one 
whose work sur\Tves only in fragments. This short line — in translation three 
syllables short of a haiku — sounds self-evident for a milUsecond and then is 
utterly mysterious. I suppose the poet could have been writing about animal 
behavior, but that seems improbable; mOitary strategy was more likely his topic. 
The most satisfying interpretation, however, is that human thinkers come in 
two species, or so Isaiah Berlin argued in his essay "The Hedgehog and the Fox." 

The fox attends to the world as it presents itself. The fox is short on pre- 
conception, long on observation. An aerial view of its itinerary shows a scram- 
ble of paths and purposes, inquiry and distractions. Hedgehogs, by contrast, 
are committed to "a single, universal, organizing principle in terms of which 
alone all that they are and say has significance." Successful careers in science 
often belong to the hedgehogs, people with a centripetal disposition and sin- 
gleness of mind who pull data into a system. Viewed from high above, their 
work is as legible and coherent as a crop circle. (Medical practice, on the 

other hand, often calls for a fox-like willingness to 
follow each scent where it leads, to pursue a 
mental life that is, on the whole, centrifugal.) 
For the special report in this issue, we asked 
seven alumni or faculty members at HMS to teU us 
about the moment when they became hedgehogs. 
For each of them, at a certain point an important idea 
or principle took hold and became the focus of their 
experience and aspirations. In retrospect, they 
spent a little time as hedgehogs in foxes' clothing but 
then settled down to the single-minded business of 
their careers. That, at least, is one reading of their sto- 
ries. An alternative interpretation is that they went through a metamorphosis, 
switching species when events made it clear to them what their path would 
be. We leave it to our readers to discern which hypothesis of discovery and 
change best fits the evidence of these lives. 




9 m 




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ALUMNI BULLETIN 



EDITOR-IN-CHIEF 

William Ira Bennett '68 

EDITOR 

Paula Brewer Byron 

ASSOCIATE EDITOR 

Ann Marie Menting 

ASSISTANT EDITOR 

Janice O'Leary 

BOOK REVIEW EDITOR 

Elissa Ely '88 

EDITORIAL BOARD 

Judy Ann Bigby '78 

Rafael Campo '92 

Elissa Ely '88 

Daniel D. Federman '53 

Timothy G. Ferris '92 

Alice Flaherty '94 

Atul Gawande '94 

Robert M. Goldwyn '56 

Petri Klass '86 

Victoria McEvoy '75 

James J. O'ConneU '82 

Nancy E. Oriel '79 

Anthony S. Patton '58 

Mitchell T. Rabkin '55 

Eleanor Shore '55 

DESIGN DIRECTOR 

Laura McFadden 

ASSOCIATION OFFICERS 

A. W. Karchmer '64, president 

WiUiain W. Chin '72, president-elect 1 

Steven E. Weinberger '73, president-elect 2 

Susan M. Okie '78, vice president 

Rodney J. Taylor '95, secretary 
Douglas G. Kelling '72, treasurer 

COUNCILLORS 

Rosa M. Crum '85 

Wesley A. Curry '76 

Timothy G. Ferris '92 

Edward D. Harris, Jr. '62 

Lisa L lezzoni '84 

Triste N. Ueteau '98 

Christopher J. O'DonneU '87 

Rachel G. Rosovsky '00 

John D. Stoeckle '47 

DIRECTOR OF ALUMNI RELATIONS 

George E. Thibault '69 

EXECUTIVE DIRECTOR OF 
ALUMNI RELATIONS 

Mary Moran Perry 

REPRESENTATIVES TO THE 
HARVARD ALUMNI ASSOCIATION 

John D. Stoeckle '47 
Joseph K.Hurd, Jr. '64 

The Harvard Medical Alumni Bulletin is 

published quarterly at 25 Shattuck Street, 

Boston, MA 02115 c by the Har\'ard 

Medical Alumni Association. 

Phone: (617) 384-8900 • Fax: (617) 384 8901 

EmaU: buLletin@hms.harvard.edu 

Third class postage paid at Boston, 

Massachusetts. Postmaster, send form 3579 

to 25 Shattuck Street, Boston, MA 02115 

ISSN 0191-7757 • Printed in the U.S.A. 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



SECOND OPINIONS FROM OUR READERS 



TETTERS 






Harvarc 



eve 



ins 



STRUCTURAL DEFECTS 

I greatly appreciated the insight and humor of the Spring 2006 
issue on the seven deadly sins. Just prior to my time at HMS, I 
was steeped in thoughts of sin while attending the Union Theo- 
logical Seminary in New York City 
Union is a bastion of liberation 
theology. On the subject of sin, 
liberation theology shifts the focus 
away from the individual and holds 
that much of sin is structural. It is 
embedded in power and privilege 
and is woven into the very fabric 
of our societies and institutions. 

A good example of structural sin 
comes at the beginning of the piece 
Atul Gawande '94 wrote on greed. 
His department chair sets out the 
formula for salaries in surgery: "The job, he explained, came 
v^th a guaranteed salary for three years. After that, I would be 
on my own: I'd make what I brought in from my patients and 
would pay my own expenses." 

This eat-what-you'ldll approach has powerful and detrimental 
ramifications. It strongly discourages providing care for a "poor 
payer mix." In other words, faculty members who care for med- 
ically underserved patients pay the price in terms of lower com- 
pensation because their patients are not considered as valuable. 

If we doctors truly want to face our own sins and address 
health care inequities, we need to examine the systems we con- 
trol. It's not just about governmental policy or insurance com- 
panies. It's about us. 

KATHERINE JAHNIGE MATHEWS '94 
ST. LOUIS, MISSOURI 



Pay It Forward 

In the excellent article by Atul 
Gawande '94 in the spring issue of the 
Bulletin he cites a surgeon with an annu- 
al net income of $1.2 million who 
believes that doctors need to under- 



stand that they are businessmen and — 
presumably — should charge what the 
traffic will bear. It is worth reminding 
this physician and others who might be 
attracted to that philosophy that U.S. 
taxpayers likely helped finance their 
entry into the "business." Perhaps up to 



half the costs of education and training 
through medical school and residency 
is subsidized by the federal and state 
governments. Not a bad deal — someone 
else makes the investment and you reap 
the reward. I have long held that med- 
ical students should have the opportu- 
nity to turn down government subsi- 
dies, but that, if they take them, they do 
so with the understanding that, in their 
future practices of medicine, they will 
not discriminate against people without 
insurance or those covered by Medicaid 
and Medicare. This would provide a 
better "business" model than that sug- 
gested by the physician who extols the 
"free -enterprise" model. 

RASHI FEIN, MD 

BOSTON, MASSACHUSETTS 



Dressed for Success 

I read the Spring 2006 issue of the 
Bulletin cover to cover and enjoyed it, as I 
do every issue. 

The article on the "deadly sin" of 
physician pride — "Vanity Fare," by Perri 
Klass '86 — reminded me of my days as a 
third-year medical student doing a core 
clerkship in surgery at Massachusetts 
General Hospital. That was when I first 
noticed that attire seemed to reflect 
hierarchy. Male medical students, 
interns, and junior residents wore white 
pants, white coUarless shirts, and short 
white jackets; senior residents tended 
to wear white pants, shirts and ties, and 
short white jackets; the chief resident 
wore dress slacks, a shirt and tie, and a 
short white jacket; and the professors 
wore dress slacks, shirts and ties, and 
long white lab coats. Imagine the boost 
to my pride when I started my derma- 
tology residency at UCLA and learned 
that I would be wearing a long white 
lab coat. Perhaps, I thought proudly, 
some "civilians" passing me in the hall- 
way might mistake me for a really 
young professor! 

In his piece on lust ("Lust Me, I'm a 
Doctor"), Stephen Bergman 73 states, 
"In the bizarre American calculus, the 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 




TETTERS 



SECOND OPINIONS FROM OUR READERS 



lust for a thong can nearly bring down 
a commander in chief...." I presume 
Dr. Bergman is referring to the perjury 
that resulted from that lust and that led 
to the impeachment of a commander in 
chief, his suspension from the Arkansas 
bar, payment of a $25,000 fine to the 
Arkansas Bar Association, and suspen- 
sion and subsequent resignation from 
the U.S. Supreme Court bar. As to 
"...but the lust for oil and empire and 
revenge that strews bloodied bodies in 
its wake," perhaps Dr. Bergman may be 
sublimating some lust in the form of 
poetic hyperbole. 

MASSAD GREGORY JOSEPH '77 
SOUTH PASADENA, CALIFORNIA 



The Skinny on Fat 

WiUiam Bennett '68, perhaps motivated 
by a desire to relieve the obese of their 
guilt, makes the case that we have little 
or no control over whether we become 
obese ("Gorged on Guilt" in the Spring 
2006 issue of the Bulletin), and all evi- 
dence to the contrary is brushed aside. 
For example, choosing a life of vigorous 
exercise — or choosing to prepare one's 



own food in reasonable portions from 
vegetables, lean protein, whole grains, 
and healthy fats — receives mention only 
in an admission that genetic destiny is 
"modified by environmental influences." 

The ease with which we modify our 
environment, of course, sets us apart 
from all other organisms, and I have yet 
to meet an individual determined to 
maintain a healthy body weight who 
mysteriously ended up needing a gastric 
bypass. American culture heavily adver- 
tises oversized portions of energy-dense 
foods at low cost and places insufficient 
emphasis on exercise. Not surprisingly, 
the prevalence of obesity is rising. It 
seems much more likely that these facts 
are related than that genetics is solely to 
blame, especially when Americans are 
becoming substantially more obese in a 
matter of decades and the prevalence of 
diabetes is rising, and when it is easy to 
watch the impact of a Western lifestyle 
on immigrant populations. 

In addition, if Dr. Bennett is going to 
promote a culture free of judgment, was it 
appropriate to compare the South Beach 
Diet, which was developed as a medical 
treatment for coronary artery disease, to a 




THROUGH A GLASS DARKLY 

On page 13 of the Spring 2006 issue is a 
picture of a man using a microscope. Is 
the picture a joke, or did the user really 
not understand that he had the scope 
turned backward and his hand possibly 
interfering with the Ught source and 
mirror? Also the lens seems to be up too 
high. Is this a real photo or a poorly con- 
trived picture? [Editor's note: Thephoto is 
an archival image from a stock photo agencyl] 

Thank you, by the way, for the page 
on my ancestor Langdon Frothingham, 
who graduated from the Harvard School 
of Veterinary Medicine's class of 1889. 

TOM FROTHINGHAM '5I 
DURHAM, NORTH CAROLINA 



concentration camp? Is fighting heart dis- 
ease really as bad as the Holocaust? 

Genetic makeup and environmental 
exposures influence our propensity to 
abuse alcohol. Yet, we expect people to 
make an effort to overcome alcoholism, 
whether the task is difficult or not, and 
we also know that patients at risk of 
alcoholism can avoid the danger entire- 
ly by choosing to abstain from the 
drinking that their peers indulge in 
without consequence. Doctors can 
and should approach obese or at-risk 
patients with the compassionate and 
nonjudgmental expectation that they 
try to improve their lifestyles. Creating 
a culture in which obesity "just hap- 
pens" means that we give the obese and 
at-risk populations our condolences 
rather than an action plan, depriving 
them of their very real, if not complete, 
control over their diet, exercise, weight, 
and health. 

IAN JENKINS, MD 

SAN DIEGO, CALIFORNIA 

Brittle White Lies 

I enjoy the Bulletin and read most of each 
issue. As much as I enjoyed the seven 
deadly sins edition, one feature unrelated 
to the special report — the "Night of 
Reckoning" by Kim-Son Nguyen '07 — 
contained what I consider an ethically 
questionable "pearl" that deserves com- 
ment. The author teUs a patient with 
abdominal pain, acute symptoms, and an 
alarming abdominal CT that she does not 
have appendicitis and will not require 
emergency surgery. He seems to feel that 
this "white he" somehow provided at 
least a temporary solution to the prob- 
lem. Yet who benefited from this dissim- 
ulation? The patient? Or Mr. Nguyen? 

In more than 30 years in clinical and 
academic radiology, I have seldom seen a 
situation that this strategy has improved. 
I have witnessed, however, several situa- 
tions where such temporary rehef (for 
the house officer) has led to patient disil- 
lusion, anger, and resentment brought 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



about by similar efforts on the part of 
young physicians trying to escape the 
difficult task of dealing with a patient 
truthfully. Although the late William 
McDermott '42 would occasionally use 
the "We won't have to operate" hne with 
great success in dealing with the famihes 
of hopeless cases, I never recall him or 
any of my other HMS mentors suggesting 
being less than truthful with patients. 

I would recommend that the next time 
Mr. Nguyen encounters a similar situa- 
tion (and he will, if he stays in the clinic), 
he simply admit to the patient that he has 
to talk her case over with his team rather 
than giving himself an easy out with an 
ethically questionable "answer" to her 
question. Mr. Nguyen's temporization 
should not be emulated. 

JAMES A. NELSON '65 
SEATTLE, Vi'ASHINGTON 



Hat Trick 

On the inside front cover of the Spring 
2006 issue of the Bulletin is a lovely old 
photograph from Children's Hospital 
Boston. The brief caption contains some 
inaccurate information, however. Clul' 
dren's Hospital Boston was indeed estab- 
lished in 1869, but not in the home of one 
of its founders, Francis Henry Brown, 
Class of 1861. Instead, the original build- 
ing was a townhouse — now nonexis- 
tent — on Rutland Street in Boston's 
South End, only a short walk from 
Dr. Brown's home on Waltham Street. 

I would also like to point out that the 
individual pictured with the young 
patient is a second-year nursing stu- 
dent. This is apparent from the two thin 
black stripes on her cap, which would 
have been replaced by a single thick one 
upon graduation. 

Those who wish to see more wonder- 
ful old photos can refer to a small book 
printed last year by Arcadia Pubhshing, 
Images of America: Childrcris Hospital Boston. 

MARK A. ROCKOFF, MD 
CHAIR, ARCHIVES COMMITTEE 
CHILDREN'S HOSPITAL BOSTON 
BOSTON, MASSACHUSETTS 




Caps and Gowns 

Thank you for reprinting the great pic- 
ture of the Children's Hospital nurse 
and her droopy-drawered patient. 
Those uniforms, though not as beautiful 
as those worn by the nurses at Massa- 
chusetts General Hospital or Peter Bent 
Brigham Hospital, were worn proudly, 
even with the black stockings. I married 
one of those "square hats" (Virginia 
Codington), and we had four wonderful 
sons who recently came to see me in my 
95th year. 



One of the good things about being my 
age is the absence of aU the sins that you so 
graphically outlined in your spring issue. 
There is still joy, however, in being part of 
a great profession — and in being able to 
read about it in the Bulletin. Keep it up! 



HENRY WORK '37 
BETHESDA, MARYLAND 



The Bulletin welcomes letters to the editor 
Please send letters by mail (Harvard Medical 
Alumni Bulletin, 25 Shattuck Street, Boston, 
Massachusetts 02115): fax (617'384'8901); or 
email (hulletin@hms.harvard.edu). Letters may 
be edited for length or clarity. 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



f, 



ptit.se 



I MAKING THE ROUNDS AT HMS 



One Hundred Years of Science 



■■^HH HEN HARVARD MEDICAL SCHOOL'S 

^%w» original Quadrangle was ded- 
^^nknfl icated a century ago, HMS 
^BA^I researchers were about to 
unveil a method for measuring the chem- 
ical compounds in blood samples. In cel- 
ebrating the centennial of that dedica- 
tion, HMS recently sponsored symposia 
that looked toward the contributions its 
researchers would make during the next 
century of scientific discovery. 

In the opening symposium on neuro- 
science, HMS dean Joseph Martin noted 
that four big questions drive the field: 
How do cells work together so the brain 



information travels up to the brain, 
where it might activate behaviors to eat 
or flee or fight or mate. 

David Anderson, the Roger W. Sperry 
Professor of Biology at the California 
Institute of Technology, has hterally bot- 
tled the smell of "fly fear" in experiments 
to understand the circuitry of how genes 
act to help the animal react and survive 
aversive stimuli. By combining the tools 
of systems neuroscience and molecular 
genetics, Anderson and collaborators 
have identified one component — carbon 
dioxide — and part of the sensory neu- 
ronal circuit necessary for avoidance 



wave into an electrical signal the brain 
can recognize. The protein that makes 
up the channel itself remains a mystery. 

In zebra finches, Allison Doupe 79, a 
professor of psychiatry and physiology at 
the University of California, San Francis- 
co, is assessing auditory motor-control 
areas. She noted that a brain region vital 
to helping zebra finches learn their 
scratchy songs seems to allow adults to 
switch between producing precise songs 
for an audience and testing new tunes 
when the birds sing alone. That same 
brain region may govern the babbling of 
children trying to mimic their parents. 




can function as it does? How can a brain 
be repaired or cured following injury or 
disease? What makes us dtEerent from 
one another? How do brains adapt to the 
changing world? 

Sensory neuroscience offers some clues. 
"Our problem is to understand how 
objects in the world are interpreted by 
specialized cells in organs and how 
information is processed by the brain," 
said Rachel Wilson, HMS assistant pro- 
fessor of neurobiology. Wilson's studies 
of the olfactory circuit of fruit flies sug- 
gest a model of cross-talk and amplified 
signals that enable the olfactory system 
to better differentiate among odors as 



behavior. But another elusive component 
is also needed to activate the neurons. 

Similarly, in hearing, key details of the 
transition between sensing and perceiv- 
ing are evading persistent inquiry. Using 
laser tweezers, Howard Hughes investi- 
gator David Corey, HMS professor of 
neurobiology, and his colleagues can 
measure the tiny mechanical forces at the 
tips of mouse hair cells, named for the 
bundle of stiff cilia that sway in unison 
at specific frequencies. The researchers 
have found that hnks between the tips of 
neighboring ciha can open and close cal- 
cium channels with sufficient force to 
turn the mechanical stimulus of a sound 



"The last century was the century of 
the gene and cracking the genetic code," 
said HMS neurobiology chair Carla 
Shatz. "This new millennium is the mil- 
lennium of the mind: If we know our 
brains, we really will know ourselves." 

The Microbes Are Coming 

When it comes to self-knowledge, bac- 
teria may hold the key, said Dennis 
Kasper, director of the Channing Lab at 
HMS and Brigham and Women's Hos- 
pital. "The striking fact about the nor- 
mal microbial colonization of mam- 
malian bodies," he said, "is that the 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



number of bacterial cells outnumber 
host cells by 100 to one." 

Kasper's group has been studying the 
biological effects of polysaccharides 
made by a bacterial species in the gut. In 
harmful bacterial infections, these long- 
chain sugar molecules are known as vir- 
ulence factors. But in colonization by 
beneficial bacteria, they may help main- 
tain the host's health. 

The rapid accumulation of basic 
research advances is fuehng the scientif- 
ic response to potentially dangerous new 
pathogens, said Michael Farzan, assis- 
tant professor of microbiology and mole- 
cular genetics at HMS. Only eight 
months after the World Health Organi- 
zation issued a global health alert for the 
SARS virus, Farzaris group pubhshed 
the identity of the viral receptor. 

Farzan notes that technological 
advances from work on HIV, the Human 
Genome Project, mass spectroscopy, and 
protein identification algorithms sup- 
port the modern detection work essen- 
tial to understanding the mechanisms of 
viral entry and the development of new 
ways to fight infections. 

Don Ganem 76, professor of microbiol- 
ogy/immunology and medicine at the 
University of California, San Francisco, 



made a strong case for gathering plenty of 
old-fashioned epidemiological evidence, 
developing tight chnical case definitions, 
and using critical thinking in a program 
of new pathogenic discovery. "If you look 
hard enough for microorganisms," he 
said, "you vvQl find them." 

Genomics and Medicine 



New genomic strategies and tools took 
center stage in the final symposium on 
cancer and drug design. Researchers at 
Jackson Laboratory in Bar Harbor, Maine, 
have developed a new systems genetics 
approach to create mouse models of com- 
mon diseases in humans and to study the 
essential nature of mammahan chromo- 
somes, said Richard Woychik, director of 
the Jackson Laboratory. 

Joan Brugge, chair of the HMS 
Department of Cell Biology, is using a 
three-dimensional culture system to 
model alterations in the architecture of 
glandhke structures in the breast caused 
by genes imphcated in breast cancer. 

"The three-dimensional structure 
allows us to distinguish the biological 
activities of genes not distinguishable in 
cells cultured as monolayers in a Petri 
dish," she said. The models resemble the 



various histologies of breast cancer and 
can be used to test the effects of chemo- 
therapy agents. 

Stephen Elledge, the Gregor Mendel 
Professor of Genetics and Medicine at 
HMS, has generated a large database of 
proteins phosphorylated in vivo during 
DNA damage. He has used the database 
to identify proteins that may play a role 
in cancer. Some of the usual suspects 
have appeared, as well as new players in 
DNA rephcation and recombination, the 
cell cycle, cellular assembly and organi- 
zation, cell death, and RNA post-transla- 
tional modification. 

One company has adapted the high- 
throughput approach to structural biol- 
ogy. Stephen Burley '87, chief scientific 
officer at SGX Pharmaceuticals, described 
a drug-discovery process that uses a ded- 
icated beam line at the Advanced Photon 
Source in Chicago for x-ray crystallo- 
graphic screening of drug fragments to 
find new protein kinase inhibitors and 
other oncology targets. Clinical testing 
for one such compound in people with 
chronic myelogenous leukemia is expect- 
ed to begin in 2007. ■ 

Carol Cruzan Morton is a science writer 
for Focus. 



The Class of 2010 



IN SEPTEMBER HARVARD MEDICAL SCHOOL WELCOMED THE 166 

members of its Class of 2010 in the traditional manner: 
by holding a White Coat Ceremony. New white coats were 
worn by graduates from 65 different undergraduate institu- 
tions in 32 states and Puerto Rico, as well as from schools 
in Canada, Ghana, Jamaica, New Zealand, Serbia and 
Montenegro, Thailand, Trinidad and Tobago, and the United 
Kingdom. Twenty-eight percent of the students are Asian 
Americans, 1 1 percent are African Americans, and nearly 
4 percent are Latinos. Native Americans make up less than 
1 percent. Fifty-three percent of the incoming group is female 
and the group's ages range from 21 to 34. ■ 




AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



ptit.se 



I MAKING THE ROUNDS AT HMS 



The State of the School 




OSEPH MARTIN, DEAN OF HMS, 

described his ninth annual 
State of the School speech as 
his most poignant one, having 
recently announced his intention to step 
down from his position in July. During 
his talk he outlined the seven priorities 
he had developed early on to help contin- 
ue the School's growth. He also reviewed 
what the HMS community has accom- 
phshed and what more needs to be done. 

Martin's first priority was expanding 
the basic science programs. He noted 
the creation of the new Department of 
Systems Biology, the Harvard Institute 
of Proteomics, the Program in Chemical 
Biology, and the New England Regional 
Center of Excellence for Biodefense and 
Emerging Infectious Diseases. In addition, 
the neurobiology and cell biology groups 
have both expanded and taken advantage 
of interinstitutional collaborations. 

Martin's second priority was improv- 
ing hospital relationships. At the time of 
his arrival the recent hospital consohda- 
tions had created an atmosphere of com- 
petition rather than cooperation. Martin 
established seed grants that led to Quad- 
based and hospital-based faculty col- 
laborations. The Dana-Farber/Harvard 
Cancer Center, for example — which has 
received the largest federal comprehen- 
sive cancer center grant ever — involves 
more than 800 researchers from across 
the HMS community. 

The dean's third priority was to nurture 
education. He instituted new ways of 
rewarding teaching. The Academy at HMS, 
devoted to improving medical education, 
has been key to enhancing the teaching 
skills of the faculty. The first class to expe- 
rience the new integrated curriculum 
arrived on campus in August. The first of 
their courses, a two-week introductory 
class, ended in a standing ovation. 

Martin's fourth priority was to develop 
community and pubUc service opportu- 
nities for students. A service requirement 
is now a part of the new curriculum. 



Leaving the Helm 



JOSEPH MARTIN, WHO HAS SERVED AS DEAN 

of HMS for more than nine years, has announced 
his plan to step down in July 2007. Until then, he 
will focus on such key priorities as education 
reform, science planning, and faculty recruitments. 

Martin, a neurologist and neuroscientist by 
training and the former chief of the neurology 
service at Massachusetts General Hospital, 
was recruited to HMS from the University of 
California, San Francisco, where he served as 
dean of the medical school and then chancel- 
lor of the UCSF system. Martin has been 
known as a bridge builder and champion of 
interdisciplinary science. 

When Martin steps down, he will focus his attention on the efforts of the 
Harvard Center for Neurodegeneration and Repair, which links more than 700 
neuroscientists across all the Harvard-affiliated institutions in an effort to find new 
therapies for disorders such as Alzheimer's, Parkinson's, and other neurodegenera- 
tive diseases. Derek Bok, interim president of Harvard, has convened a faculty 
advisory committee to begin the search process for a new dean, with the expecta- 
tion that the ultimate selection will be made by the next president of Harvard. 

"Joe Martin has served Harvard Medical School and the University with 
integrity, imagination, and great distinction," Bok said. "His successor will 
inherit a School that is exceptionally strong in terms of medical education, scientific 
research, and connection to the clinical enterprise." ■ 




The fifth priority was to take advan- 
tage of technology to improve commu- 
nications and access to resources. Mar- 
tin noted that the School has made great 
gains in its research computing cluster, 
making technologies available for data- 
intensive research. 

When introducing his sixth priority, 
Martin said, "The diversity issue, in many 
ways, has been the most challenging." An 
early system- wdde review of junior facul- 
ty "stuck" in the lower ranks has since 
resulted in many women and minorities 
receiving promotions. 

In discussing his final priority, Mar- 
tin outlined several grants and gifts the 
School has received in the past decade. 



but conceded that the task of fundrais- 
ing is never done. 

Martin concluded by pointing out the 
addition of the word "diverse" to the HMS 
mission statement, which now truly 
reflects his early goals for the School. ■ 



Nominations Sought 

AFTER NEARLY A DECADE OF DEVOTED 

service, Tenley Albright '61 has 
stepped down as chair of the HMS 
Alumni Fund. To nominate yourself 
or another HMS graduate to take 
on this role, email the interim 
chair, Daniel Federman '53, at: 
daniel federman@hms.harvard.edu. 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



PRESTDE NT^S REPORT taJ 



Ties That Bind 



^■■■■H HEN HARVARD MEDICAL SCHOOL'S GRADUATES CROSS 

^% wM the Stage each year, they receive not only a diplo- 
^k nk nH ma, but also the School's commitment to support 
i^"™^H and sustain them as physicians throughout the 
years to come. The importance of this commitment — and the 
bond it forges — has grown increasingly weU defined during 
our recent Alumni Council meetings. 

The HMS alumni office, which has completed a major reor- 
ganization, is now well poised to offer additional benefits to 
graduates. Under the leadership of George Thibault '69, direc- 
tor of alumni relations, and Mary Moran Perry, executive 
director of alumni relations, the office has conjured new syn- 
ergies and expanded resources. 

The most notable of these resources are now in develop- 
ment: an electronic directory of HMS alumni and a reinvig- 



resources. We are working with Sanjiv Chopra, faculty dean 
for continuing education, to estabhsh opportunities for HMS 
graduates to take advantage of the School's myriad offerings. 
One outcome of this outreach is that HMS alumni have a 
standing invitation to be guest attendees at the regional cours- 
es titled "Current Clinical Issues in Primary Care," or Pri-Med. 
Embodied in these courses are presentations of broad medical 
interest, such as the recent one on RNA interference by Craig 
Mello, recipient of this year's Nobel Prize in Medicine. 

All this activity has not, however, caused us to lose 
momentum on an issue many of us consider vital — helping 
to alleviate student debt. During his recent term as Council 
president, Steven Schroeder '64 directed our attention to 
the problem of excessive student indebtedness and urged 
Dean Joseph Martin to consider steps to ameliorate this bur- 




With these links to Harvard Medical School, we will 
be collectively and individually only keystrokes away 
from connecting to the School's resources. 



orated Harvard Medical Alumni Association website. These 
advances wHl give new support to the Association's efforts to 
stay in touch and to encourage you to do the same — both high 
priorities for the Council. With these links to Harvard Med- 
ical School, we will be collectively and individually only key- 
strokes away from connecting with the School's resources. 
The website in particular promises to be a wonderful boon to 
reunion planning and to provide a portal through which com- 
munication on issues, plans, proposals, and news can pass. 

Several Council members have pledged to work with 
WiUiam Chin '72, the Council's first president-elect, on how 
we can best exploit the website's potential to enhance ties 
among HMS alumni. Steven Weinberger '73, the second presi- 
dent-elect, wiU lead another group of Council members as they 
focus on ways to bring students and alumni together, actually 
and virtually, using the website. Council members Susan Okie '78 
and Rodney Taylor '95 have a head start in this area: They have 
organized a group of alumni in Baltimore and Washington, 
DC, who are ready to work with fourth-year students looking 
for training opportunities in that region. 

Council members are also looking for new ways alumni 
might use the School's continuing medical education 



den. Many of you have already acted; the 2005-06 Alumni 
Fund raised additional dollars that were dedicated to 
defraying debt. 

This activity comes at a critical juncture; after nearly a decade 
of exemplary service, Tenley Albright '61 has stepped down as 
chair of the HMS Alumni Fund. The interim chair, Daniel 
Federman '53, however, will carry the baimer for the program 
while the search for a new Alumni Fund chair is under way. 

During the past several years the Council has renewed its 
vigor and sense of mission for the challenges the School faces. 
We want to do more than receive reports on the state of the 
School and its various activities from administrative and facul- 
ty leaders. We want to assist the HMS community and to rep- 
resent you. Please help us do both by bringing your ideas and 
concerns to our attention. ■ 

A. W. Karchmcr '64 is chief of the Division of Infectious Disease at the Beth 
Israel Deaconess Medical Center in Boston. He can he reached at 
akarchme@hidmc.harvard.edu. 

For more information about the Harvard Medical Alumni Association, 
visit www.hms.harvard.edu/alumni. 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



CTTRRSTDK C O N STI TT ATTO N 



Prescriptions for Hope 




Y FATHER ENCOUNTERED THE FIRST OF THE PHYSICIANS 

in 1941. As the youngest and only unmarried sibling 
of eight Bursztajns, my father, Abraham, had been 
left in charge of the family's lumberyards in Lodz 
soon after the German invasion of Poland on September 1, 1939. 
Most of the members of his family had left for Warsaw, which 
had been something of a haven during World War I. My father, 
not having other family responsibilities, volunteered for the 
dangerous job of overseeing the family's holdings in what was 
considered an area far more likely to be involved in the fighting. 
The Nazis had compiled a list of prominent Jewish families 
with assets, and my father's family was on that list. In 1941 
the Nazis captured him, threw him in jail, and tortured him 
to reveal his family's whereabouts. He refused. 



he recruited others by pulling acquaintances off the train plat- 
form as they were waiting to embark for Auschwitz. One of the 
people he recognized was Miriam, the daughter of a furniture 
craftsman he knew from his family's lumber trade. 

Miriam had given up hope after her father's death from 
starvation, and she was already on the train, knapsack on her 
back. But when my father talked with her, she agreed to his 
plan. My father approached the Nazi officer supervising the 
deportation. "She is one of the sanitation workers who has 
been ordered to stay in the ghetto until the last," he said. "She 
needs to come with me." When the officer looked skeptical, 
my father played his final card: He flashed a family photo- 
graph given to him by a high-ranking German officer with 
anti-Nazi leanings. The officer in charge let Miriam go. 




"One of us will die, but it will be me," the physician told my 
father. "I do not have any way of treating you, but you are young. 
If you don't give up hope, you will survive." 



igj^^aBBag^f 



After a particularly severe flogging, my father fainted. He 
was surprised to awaken in the jail's infirmary. His interroga- 
tors, intent on making him disclose his family's location, had 
decided to keep him alive for continued questioning — and tor- 
ture. As he stirred, he realized that standing before him was a 
doctor, himself a Jewish prisoner, who ministered to the other 
prisoners. "I will die here," my father told the older man. 

"One of us wHl, but it will be me," the physician replied. "I 
do not have any way of treating you, but you are young. If you 
don't give up hope, you will survive." 

This physician inspired my father by first acknowledging 
their shared hopelessness but then instilhng in him a determi- 
nation to survive. My father did his part and survived. When 
he eventually returned to what was by then the Lodz Ghetto, 
he was offered a "choice" job — to collaborate with the Nazis 
by becoming a Jewish police officer. His refusal enraged the 
Nazi- installed figurehead of the ghetto, Mordechai Chaim 
Rumkowski, known among those in the ghetto as the King of 
the Jews. Rumkowski slapped my father, then sought to humil- 
iate him by assigning him to work on sewage disposal. 

Remembering the doctor's words, my father resolved to 
transform the job into a way to create hope. His first priority 
was to estabhsh a home for a Jevwsh Resistance cell. He found 
willing members among some of his sewerage co-workers, and 



Running for Cover 

By 1944 my father and the other members of the Resistance cell 
were comonced the Nazis were planning to kill those who 
remained in the Lodz Ghetto. But the resistors had no weapons 
with which to mount a revolt, and by that time they had heard 
of the carnage suffered by those li\Tng in the Warsaw Ghetto 
during its 1943 uprising. After much debate, they decided to 
resist by going into hiding. But where? The Nazis had been 
employing dogs to sniff out other Resistance hiding places. My 
father realized that the sewer system itself, if waterproofed 
areas could be created, offered a natural hiding place. The 
stench of the sewers would confuse the dogs. 

The challenge was obtaining the cement necessary to build a 
watertight bunker in the sewer system. The only available cement 
was in a well-secured Nazi warehouse outside the ghetto walls. 
My father and one of his comrades decided to risk a night raid. 

The raid was an initial success. While carrying 100-pound 
bags of cement back to the ghetto, however, my father and his 
colleague were shot at, and a Nazi patrol gave chase. Zigzag- 
ging at a sprint, my father evaded the automatic weapons fire 
until a bullet struck him in the shin. Injured and bleeding pro- 
fusely, he could no longer run. With the enemy closing in, he 
looked for a refuge. He spotted a nearby dumpster and, stiU 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



INFORMAL MEDITATIONS ON THE MEDICAL PROFESSION 




IN MEMORIAM: Visitors 
stand in the doorv^ay of 
a Holocoust memorial in 
Lodz, Poland, erected on 
the site of the Radegast 
train station, which 
was used as a point of 
embarkation for Jev\^s 
on their way to the 
death camps. Through 
quick thinking, the 
author's father was able 
to rescue his future >vife 
just before the doors 
closed on a train bound 
for Ausch>vitz. 



clutching his bag of cement, jumped in, puUing the cover over 
him. The Nazi patrol rushed past. 

When the area cleared, my father staggered vidth the heavy 
bag back to the Resistance's rendezvous. Now that the cement 
had been saved, he needed to save himself. Surely that morning 
the Nazis would investigate, notice the blood on the bridge, 
and look for absentees from the morning's work detail to inter- 
rogate as suspects in the raid. My father's comrades contacted 
one of the few doctors stiU left in the shrinking ghetto. 

In the hours before dawn, the doctor risked his life to 
visit my father. He no longer had surgical instruments, so he 
straightened a coat hanger to fashion a crude probe. Sterihzing 
it as best he could, he used the makeshift tool to extract the 
bullet. He had httle time, and few words were exchanged. In 
the absence of anesthesia, afterward the surgeon gripped my 
father's shoulders with affection to help quiet the searing pain. 
When they parted, my father kissed the hands that had saved 
him. That morning my father was able to appear for the roll call 
with a baggy pair of pants hiding the dressing on his wound. 

Working at night, the members of the Resistance cell used the 
precious cement to construct a bunker in the sewer system. 
Concealed by water, the bunker had pipes that brought in air, 
water, and electricity. For the final six months of the Nazi reign 
of terror, 14 people hid in that space — and survived. By then, my 
father had helped spread the word about the sewer system, and 
many others found shelter there or used it as an entryway into 
the basements of abandoned houses. 

The Gift of Life 



My father could not save his family of origin. But he and his 
comrades in the Resistance cell, including Miriam — ^who later 



became his wife and my mother — did save the lives of others. 
The memories of his family, of his comrades in the Resistance, 
and of the physicians who had saved his life had become hope- 
sustaining assets that neither the Nazi terror nor the passage 
of time could obliterate. 

The Lodz Ghetto was liquidated in August 1944, and for 
each night after, as he emerged from the bunker to forage for 
food, my father felt as if the dead were keeping watch. Finally, 
the living, in the form of the Russian Army, came to the rescue. 
The soldiers found more than 800 Jewish survivors of the 
ghetto holding on in the sewer system. 

My father never saw either physician again. Decades later, his 
eyes would fill with tears when he recounted learning that the 
doctor who had removed his bullet had been found in hiding in 
the evacuated ghetto and was murdered along with his family. 

Beyond carrying personal meaning for me, my father's story 
of survival has resonated with me professionally. It reminds me 
that physician integrity can be maintained in the most trying 
situations. If the physicians my father encountered during the 
Holocaust could preserve the decency of authentic doctoring, 
then so can we all, whatever the circumstances. Supporting our 
patients' hope and autonomy — even in the most resource -limit- 
ed conditions and against all odds — is our fundamental duty, 
even when we face with them the most hopeless of realities. ■ 

Harold]. Bursztajn 76 is an EMS associate clinical professor of psychiatry 
at Beth Israel Deaconess Medical Center and a co-founder of the Program 
in Psychiatry and the Law at Harvard Medical School. As a child in 
Lodz he remembers people rushing up to his father to thank him for sav- 
ing their lives. (The author's original essay appeared in the Winter 1996 
issue o/ The Journal of Clinical Ethics. This adaptation appears 
with permission ofthejournal, which retains rights.) 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



BOOKMARK 



I REVIEWING THE PRINTED WORD 



The Mind Has Mountains 

Reflections on Society and Psychiatry, by Paul R. McHugh '56 
(Johns Hopkins University Press, 2006) 



MAYBE YOU'VE HEARD ABOUT THE MENTAL HOSPITAL THAT BUILT 

separate elevators for its neuropsychiatrists and its psycho- 
analysts because they refused to ride together. Someone 
described the elevator solution to me during my first psychi- 
atric rotation. The notion made a deep 
impression, although I later learned, to 
my disappointment, that those dop- 
pelganger elevators do not exist. But 
this much is true: Those who enter a 
field about human nature also enter a 
field divided by human nature. 

Paul McHugh '56, professor of psy- 
chiatry emeritus at the Johns Hopkins 
University School of Medicine, has 
been thinking for many years about 
psychiatry's problems — including this 
kind of sectarianism — and its solu- 
tions. He is a cantankerous, intelhgent 
writer, so precise that he names each 
tiny hgament before transecting it. He 
dissects clearly, confidently, and down 
to the bone. 

The Mind Has Mountains is a compila- 
tion of his essays (which are them- 
selves compilations from his teaching 
and chnical experiences) from Com- 
mentary The Weekly Standard, The American 
Scholar, the New England Journal of 
Medicine, and other worthy publications. The chapter titles 
are proclamations, such as "Psychotherapy Awry," "How Psy- 
chiatry Lost Its Way," "Romancing Depression," and "The 
Death of Freud and the Rebirth of Psychiatry." The premise is 
stern: Psychiatrists have "made claims that were not true, 
pressed for attitudes and behaviors that were destructive, 
and held behefs about human mental Me that were incredi- 
ble." The conclusion is dire: "When caught up by the social 
suppositions of their time, psychiatrists can do much harm." 

How have we become forces of such destruction? Partly it 
is because we are only human. "Psychotherapists," McHugh 
explains, "have a natural tendency to give themselves over to 
the softer virtues of kindness, gentleness, and soothing sup- 
port. . .at the expense of the sterner virtues of truth, responsi- 
bihty, and justice." Partly it is because of hubris; we don't dis- 
courage the world from beUeving we alone "know deep 
secrets... [that] tend to turn on matters sexual [and] uncon- 
scious." There is also our vulnerability to shoddy and faddish 




social thought. Since the days of Freud, instead of the rigorous 
differential diagnosing found in other fields, "the romanticist 
tendency in psychotherapy is to rely upon feelings for evidence, 
on metaphors for reahty, on inspiration and myth for guidance." 
McHugh's essays are full of critical examples, such as 
adult attention deficit disorder, gender identity disorders, 
social phobias, repressed memories, and multiple personahty 
disorder (he lances and drains that last one as if it were filled 
with pus). Even the Diagnostic and Statistical Manual of Mental 
Disorders, with its Chinese menu of symptoms, comes under 
his scalpel. Diagnosis driven only by 
appearances and symptoms is "so crude 
as to foster inept educational programs 
and clumsy clinical practices." 

So, what is left of the body after all 
this dissecting is done? Good news 
for psychiatry: McHugh reports that 
with proper reconstructive efforts, the 
organs scattered here and there can be 
reassembled. Four decisive and differ- 
ent ways of formulating patients must 
be part of any psychiatric education; 
to the author's mind, they will redeem 
the field. Brief summations carmot do 
justice to the richness of his disease, 
dimensional, behavior, and life-story 
perspectives. I wish I had learned 
them years ago. Together, he writes, 
they constitute a method of differen- 
tial diagnosis — and therefore treat- 
ment — free of bias and as close to 
"empirical psychiatric principles" as is 
humanly possible. Medical education 
owes this to the psychiatrist, and the 
psychiatrist owes it to the patient. It is the least we can do 
for patients — and the most. 

This is a book full of certainty. There is not a single con- 
fused thought in it. Yet it may bring up confusing feehngs. 
The reader races through the first 150 pages driven — some- 
times flogged on — by its fierce arguments. But the certainty 
is not always pleasant to hear, particularly in the last sec- 
tions, when it extends into areas of ethics and pohtics. After 
finishing McHugh's pronouncements on do-not-resuscitate 
orders, hving walls ("signposts of our own culture of death"), 
and the "just war" he finds in Iraq, I found myself missing 
some of those "softer virtues of kindness, gentleness, and 
soothing support." An even more Hberal reader may find him- 
self wishing to ride in a separate elevator. Ethics and pohtics 
come to roost in our own httle homes, and we who share the 
profession may live on very different streets. ■ 

Elissa Ely '88 is a psychiatrist at the Massachusetts Mental Health Center. 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



BOOKS BY OUR ALUMNI 



ROOKSHET.F 






When Invisible Children Sing 

by Chi Huang '97 with Irwin Tang 
(Salt River Booles, 2006) 

The book describes Huang's education in 
compassion and hope, gained while treat- 
ing orphans and street children in La Paz, 
Bohvia. He meets child prostitutes like 
Mercedes, a sexually abused 15'year-old 
who cuts herself; the infant Maria, who 
dies in a hospital because neither her 
mother nor the hospital can afford to 
feed her; and Alejandro, who leaves the 
orphanage to become a successful chef. 

Healing Psychiatry 

Bridging the Science/Humanism Divide, 
by David H. Brendel '95 (MIT Press, 2006) 

The author proposes a clinical pragma- 
tism to mental health care, one that syn- 
thesizes its scientific and humanistic 
aspects. He argues that psychiatrists 
must learn to consider the process of 
diagnosis to become more responsive to 
the consequences of that diagnosis. 
Drawing on case studies and the work of 
thinkers such as WUham James, Class of 
1869, and contemporary bioethicists, 
Brendel calls for an open-minded, yet sci- 
entifically informed approach to under- 
standing mental disorders. 

Moral Values, Politics & You 

The Moral and Tribal Nature of All Politics, 
by Fidel Davila '76 (MoDaus Publishing 2006) 



moral philosophy and ethics, according 
to the author. He also discusses how 
the sharing of personal and moral val- 
ues forms "tribes" of people and 
explains the roles of such tribes in pol- 
itics. Included are essays on the ethics 
of abortion, marriage, end-of-life direc- 
tives, and lying. 

The Psychopathy of Everyday Life 

How Antisocial Personality Disorder Affects 
All of Us, by Martin Kantor '58 (Praeger 
Publishers, 2006) 



This book makes the case for the exis- 
tence of "mild psychopathy" in individ- 
uals whose behavior falls somewhere 
between normal and psychopathic. 
Kantor calls them the "forgotten people 
of psychopathology" They appear to be 
upright citizens marred by a smidgen of 
dishonesty, but they really have a treat- 
able, mild psychopathy. The author out- 
lines underlying personality structures 
and explains how traditional therapy 
can be tweaked for effective treatment. 

Global Burden of Disease 
and Risk Factors 

Edited by Alan D. Lopez, Colin D. 
Mathers, Majid Ezzati, Dean T Jami- 
son, and Christopher J. L. Murray '91 
(Oxford University Press and 
the World Bank, 2006) 



All politics begins with personal values 
and how they shape an individual's 



One of the more useful components of 
this reference text is the section contain- 
ing more than 100 pages of charts that 
show how risk factors comphcate dis- 
ease and influence mortality rates in 



comparative age and geographic groups. 
Those charts compare, for instance, how 
obesity affects breast cancer, heart dis- 
ease, and osteoarthritis among Euro- 
peans, South Asians, and several other 
populations across eight age cohorts. The 
editors also include analyses of the data. 

Triathloning for Ordinary Mortals 

And Doing the Duathlon Too, by Steven 
Jonas '62 (third edition, W. W. Norton, 2006) 

Recreational runners, cycHsts, and swim- 
mers hoping to enter long-distance 
races can turn to the pages of this book 
for training guidelines and suggestions 
for choosing appropriate races. Jonas 
himself didn't do a triathlon until he 
was 46, and he now provides tips and 
inspiration for getting started and fin- 
ishing healthily and happily. 

Adolescent Medicine 

An Issue of Primary Care: Clinics in Office 
Practice, edited by Donald E. Greydanus 
and Victor C. Strasburger '75 
(Saunders, 2006) 



The editors begin their book by taking 
the long view of adolescence — analyz- 
ing its Latin and Greek roots, reflecting 
on the first teen health clinic in the 
United States, and considering issues 
facing today's 55 million young people. 
Contributors guide readers in 15 specif- 
ic areas of concern for contemporary 
youth, including sexuality and repro- 
ductive health, violent behavior, media 
influence, sports injuries, substance 
abuse, and diabetes management. 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



RENCHMARKS 



I DISCOVERY AT HMS 




Heavy Weather 



HEY WERE CALLED NERVE STORMS, 

these explosive, incapacitat- 
ing headaches. The "megrims" 
brought debilitating pain 
before wringing themselves from their 
victims through nausea and vomiting. 
And, according to nineteenth-century 
practitioners, they always began with 
an aura, a term covering such omnibus 
symptoms as zigzagging light flashes, 
tunnel vision, and other unsettling dis- 
tortions of sensory information. 

Although mentioned in works from 
the time of Hippocrates, migraines and 
their symptoms were first described 
fully in the late 1870s. By the early 
1940s, the distinct personalities of the 
migraine and the aura were better 
known: For one thing, it was under- 
stood that "sick headaches" could occur 
without auras. 



In the July 19 issue of the Journal of the 
American Medical Association, researchers at 
Brigham and Women's Hospital added to 
medicine's knowledge of nerve storms by 
showing that women who suffer from 
migraines with auras have a higher risk 
for cardiovascular disease. 

Migraines are described as periodic 
neurovascular disorders that repeat 
throughout the lives of their victims. 
Often, they are marked by headaches so 
severe the sufferer becomes temporarily 
incapacitated. For some, the pain is 
accompanied by an aura. In the United 
States, in any given year, approximately 
18 percent of women and 6 percent of 
men suffer migraines, percentages that 
represent an estimated 28 million people. 

Previous studies of women's risk for 
ischemic stroke and cardiovascular disor- 
ders hinted at links between these condi- 



tions and the incidence of migraines, 
especially migraines with auras. In their 
study, the scientists at Brigham and 
Women's sought to probe for possible 
connections between migraines and 
stroke and coronary events. 

The scientists used data collected from 
participants in the Women's Health Study, 
which tested whether the use of low-dose 
aspirin and vitamin E had any preven- 
tive effect on cardiovascular disease in 
women who were at least 45 years old. At 
the start of the study, the 27,840 partici- 
pants were judged to be free of angina 
and cardiovascular disease. Enrolled 
between 1992 and 1995, the women in 
the study were followed for ten years. 

The researchers analyzed the study 
data and found that slightly more than 
5,000 participants had a history of 
migraine headache. Within this pool of 




14 HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



children's ISflSe 




migraine sufferers, 3,610 had reported 
active migraines; that is, they had expe- 
rienced a migraine in the past year. Of 
the women with active migraines, 1,434 
also had reported auras. 

When the investigators compared data 
from women who did not report a history 
of migraines with those from women who 
suffered from migraines with auras, they 
found that women in the latter group 
were twofold more likely to experience a 
major cardiovascular event, myocardial 
infarction, ischemic stroke, death due to 
ischemic stroke, or angina. They also 
found that this increase in risk was not 
constant; it seemed to spike into being 
around the six-year point. 

For women who had migraines but no 
auras, the study's conclusions were more 
favorable. Such women showed no 
increase in their risk for experiencing a 
cardiovascular event. 

Although the researchers cannot say 
precisely why women who suffer these 
tempests of light and pain have an 
increased risk for major cardiovascular 
events, they speculate that underlying 
biological mechanisms believed to raise 
the risk of cardiovascular problems — such 
as high cholesterol, high blood pressure, 
and other artery-narrowing conditions, 
and possibly even the genetic differences 
linked with elevated homocysteine lev- 
els — may act in a concerted manner to 
increase a woman's risk over time. 

For women who do experience auras 
when they have migraines, lead author 
Tobias Kurth, an HMS assistant professor 
of medicine in Brigham and Women's 
preventive medicine unit, cautions that fur- 
ther research is needed to better under- 
stand the relationship between migraines 
v/ith auras and an increased risk for major 
cardiovascular events. But, while these 
women wait for such research, Kurth sug- 
gests they be alert for ways to control their 
risk, such as by exercising, eating plenty of 
fruits and vegetables, maintaining a healthy 
weight, and refraining from smoking. ■ 



lllli^ WEIGHTY ISSUE 

Tip-the-scales fat or just baby fat? A study in the July issue of Obesity indi- 
cates it's likely to be tfie former. A research group led by Matthew Gillman, 
an HMS associate professor of ambulatory care and prevention, sifted 22 
years of data gathered during well-child visits of 1 20,000 eastern Massachu- 
setts children under two years of age and discovered that the prevalence of 
overweight children increased 59 percent during the two decades. The pro- 
portion of children at risk for becoming overweight jumped 30 percent. 
Infants fared even worse: The number of pudgy infants increased 74 percent 
and those at risk of becoming so increased 59 percent. The scientists say the 
problem likely starts before birth; compared to their 1980s peers, pregnant 
women today weigh more and gain more during pregnancy. 

Illl^ BRINGING UP BABY 

Move over Vegameatavitamin. Omegaven is not only less of a mouthful, it 
may actually be an elixir, at least for tiny tykes with troubled tummies. A trial 
by researchers at Children's Hcj^pital Boston found that infants who require 
parenteral nutrition are better served by a preparation containing omega-3 
fatty acids than by the usual mixture that relies on soy and other plant oils. 
Their use of an omega-3-rich product, Omegaven, for two infants who had 
intestinal problems at birth completely reversed cholestasis in each — one 
even was able to be removed from the list of liver transplants hopefuls. The 
study's team leader was Mark Puder, an HMS assistant professor of surgery. 
^ The report appears in the July issue of Pediatrics. 

H>^ SAFE SLUMBERS 

An investigation into sudden infant death syndrome (SIDS) has fingered a bio- 
logical suspect: abnormalities in the brainstem's serotonin system. The findings 
help explain why male infants and infants under six months of age are more 
likely to succumb to such a death. They also offer the hope that a diagnostic 
test — possibly even a treatment — could be developed. In the United States, SIDS 
is the leading cause of death after the newborn period. 

Between 1 997 and 2005, a team of researchers from Children's Hospital 
Boston and HMS studied the medullae oblongata taken during autopsies of 41 
infants. The medulla oblongata, which forms the lower portion of the brainstem, 
is home to nerve cells that produce the neurotransmitter serotonin. The chemical 
is thought to control such homeostatic functions as breathing, blood pressure, 
and sensitivity to carbon dioxide, a buildup of which causes suffocation. 

When the scientists analyzed tissue from the 3 1 infants who had died from 
SIDS and the ten control infants who had died acute deaths from other causes, 
they found the medullae from SIDS infants — especially in the boys — were defi- 
cient in a particular serotonin receptor and in a transport protein that "recycles" 
serotonin. And although these medullae showed an abnormally high number of 
serotonin-producing neurons, most serotonergic neurons were immature. 

The researchers note that such defects could mar an infant's ability to control 
the vital homeostatic functions ruled by serotonin. The report appeared in the 
November 1 issue of the Journal of the American Medical Association. 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



RKNCHMARKS 



DISCOVERY AT HMS 



Red Red Wine 




ECENT RESEARCH AT HMS HAS 



conjured up images of tiny 
paws grasping the stems of 
tiny wine glasses. A com- 
pound in red wine has been shown to 
improve health and survival in mice fed a 
high-calorie diet. Treatment with resver- 
atrol, a plant-derived molecule found in 
red wine, prevented many of the 
health consequences of obesity, 
even as mice gained weight. 

David Sinclair, an HMS asso- 
ciate professor of pathology who 
led the research, first identified 
resveratrol in a screen of mole- 
cules that enhance the activity 
of Sirtl, the mammalian version 
of the protein Sir2 that has been 
shown to affect life spans in 
yeast and other lower organ- 
isms. Since then, resveratrol has 
been demonstrated to increase 
life span in worms, fruit flies, 
and fish. This study, published 
online in Nature on November 1, 
is the first in a series of studies 
by Sinclair's group to determine 
whether resveratrol has the 
same impact on mammals. 

Living Lean 

So far, the most rehable way to 
extend the life span of an organ- 
ism is through caloric restriction. 
Since Sir2 seems to mediate the 
effects of caloric restriction in 
some lower organisms, Sinclair's team 
has been investigating whether manipu- 
lating the equivalent pathway in mam- 
mals can achieve the same benefits with- 
out cutting back on food. Joseph Baur, a 
postdoctoral fellow in Sinclair's lab and 
first author on the paper, says that study- 
ing the compound's effects in high-fat 
diets also makes sense given the preva- 
lence of overweight and its known 
health risks. "Obesity," he says, "tends to 
accelerate a lot of aging-related diseases." 



The study compared three groups of 
mice: one fed a normal diet; another that 
began a high-calorie, high-fat diet at 
middle age; and a group that began the 
same high-calorie diet but were simulta- 
neously treated with resveratrol. After 
six months of treatment, mice that 
received resveratrol had a significantly 




higher survival rate. At 114 weeks of age, 
42 percent of treated mice had died, 
compared with 58 percent of their 
untreated peers fed a high-calorie diet. 

Resveratrol did not prevent mice from 
gaining weight on a richer diet, but it did 
prevent obesity-related health problems. 
Untreated mice who followed the high- 
calorie diet had swollen hvers fihed with 
fat deposits. The livers of the treated 
mice, however, looked normal. Mice in 
the group treated with resveratrol had 



healthier hearts, comparable to those of 
normal mice; lower levels of blood glu- 
cose and insuhn; and higher insulin sen- 
sitivity. In a test of motor skiUs, the 
resveratrol-treated mice outperformed 
untreated overweight peers and even 
showed improvement with age. 

The team also examined gene expres- 
sion changes in the hver tissue of 
the mice. They identified 153 path- 
ways that were significantly 
changed by either the high- calorie 
diet alone or the high- calorie diet 
plus resveratrol. In 144 of them, 
resveratrol produced an effect 
opposite that of a high-calorie diet; 
in other words, says Baur, "If a 
pathway went up in comparison to 
a standard diet, resveratrol made it 
go down" — and vice versa. 

Missing Pieces 

One of the study's surprises is 
that resveratrol seems to have 
uncoupled the health conse- 
quences of being overweight 
from the fat itself. "By looking at 
the physiology of these mice, you 
would think they are lean 
healthy mice, but they're fat 
healthy mice," Sinclair says. The 
implication, he adds, is that "fat 
isn't necessarily bad if you can 
block its effects." 

Matt Kaeberlein, assistant 
professor of pathology at the 
University of Washington, says the 
study suggests that taking resveratrol or 
a similar compound could be beneficial 
for people who are obese or consume a 
high-fat diet — which unfortunately 
includes most people in the United 
States and other developed countries. 
But the study leaves open many ques- 
tions, such as how resveratrol works and 
whether it can mimic the effects of calo- 
rie restriction in lean animals, which 
Sinclair's laboratory is currently testing. 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



The attempt to translate the path- 
ways controUing Hfe span in lower 
organisms into mammals has generated 
a great deal of debate. "Because the biol- 
ogy is so complicated, many of these 
pathways tie together," says Kaeberlein. 
"It's difficult to untangle." 

Sinclair beheves that the compound is 
keeping mice healthy by triggering the 
same life-extending response that a strict 
diet does. He notes, however, that, "There's 
a lot to figure out about how resveratrol 
works." His team used a proxy measure of 
Sirtl activity to show that the enzyme was 
more active in mice treated with resvera- 
trol. Sinclair doesn't rule out the possible 
involvement of other pathways, and the 
team is currently testing Strtl's role by 
treating Sirtl-knockout mice. 



Sinclair beheves that because resvera- 
trol is produced when plants are 
stressed, it may be one of many plant 
compounds that can trigger a "survival 
response" in animals that consume them. 
"It could be that we've evolved to sense 
molecules from the plant world," he says, 
adding that certain components of plants 
are not just beneficial as antioxidants or 
anti- inflammatories but are actually 
sending signals that change physiology. 

Glasses should not yet be raised in 
toast to these findings, however. The 
daily dose of resveratrol given to mice in 
this study is the equivalent in humans of 
100 glasses of wine, so its role at normal 
dietary levels is unknovvn. 

Rafael de Cabo, the study's co-senior 
author and an investigator at the 



National Institute on Aging's Labora- 
tory of Experimental Gerontology, 
hopes this study will spur new meth- 
ods for testing the effects of aging in 
the body. Using longevity as an end- 
point is onerous because studies on 
mammals can take years or, in the case 
of primates, decades. 

"We need to find out what the exact 
targets are that resveratrol is hitting 
within fat tissue and organs," de Cabo 
says, as well as understand how caloric 
restriction affects the entire body of an 
animal. Only then can scientists start to 
unravel the puzzle of how these inter- 
ventions extend life. ■ 

Courtney Humphries is a science writer 
for Focus. 




ON RED ALERT 





esearchers at Brigham and Women's Hospital 
(BWH) have found that eating more red meat may 
be associated with a higher risk for hormone recep- 
tor-positive breast cancers in premenopausal 
women. This research appears in the November 13 issue of 
the Archives of Internal Medicine. 

"This study suggests that dietary factors may be related to 
a woman's chance of developing this type of breast cancer, 
a disease that is on the rise in American women," says lead 
author, Eunyoung Cho, a researcher at BWH. 

Hormone receptor-positive breast cancers are characterized 
by tumors in which growth is stimulated by the levels of estrogen 
(ER+) or progesterone (PR+) circulating in the body. Previous 
studies that have examined the association between breast can- 
cer and red meat assessed diet in midlife or later, did not distin- 
guish by hormone receptor status, and are largely inconclusive. 
In this study, researchers evaluated the association between 
breast cancer and red meat consumption in 90,659 female 
nurses aged 26 to 46 who are part of the Nurses' Health 
Study II. The researchers followed the participants from 1991 
through 2003 and gathered data on red meat consumption 
and breast cancer development. 



Out of this group, which excluded postmenopausal women 
and those who hod previously had cancer, researchers identi- 
fied 1,021 women who had developed breast cancer. Among 
those with information on hormone-receptor status, 512 cases 
were ER-i-/PR-h. 

The researchers split the women into five groups based on 
how much red meat they ate and found that those with the 
highest intake of red meat, more than one-and-a-half servings 
per day, hod nearly double the risk for hormone receptor-posi- 
tive cancer compared with those with the lowest intake of red 
meat, which was fewer than three servings per week. 

Researchers suggest several biological factors that may be 
related to the association between red meat and ER-^/PR-l- 
breast cancer, including carcinogens found in cooked or 
processed red meat, hormone treatments of cattle for growth 
purposes, and the type of iron found in red meat. 

"The reason the amount of red meat consumed by a pre- 
menopausal woman was related to her breast cancer risk is 
unknown," says Cho, who is also an assistant professor of 
medicine at Harvard Medical School. "But this study shows 
that the association is strong and that more research should be 
done to further explore this connection." ■ 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



Scientists and physicians recall the defining moments 



f 



18 HARVARD MEDICAL ALUMNI BULLETIN • AU 




that have ignited their innovations in medicine. 



EVEN IF WE COULD ASSEMBLE A TIMELINE of innovations made at Harvard 
Medical School — and by its graduates everywhere — during the past two-and-a-quar- 
f ter centuries, we could never portray the minds and hearts behind those discover- 
;,; ies. We could never recapture the moments of inspiration, the years of dedication, 
■^ the decades of determination. We asked just a handful of Harvard Medical 
;■ School graduates and faculty members to recall their own sparks of inspiration, 
■5 whether from the puzzle of an infant dving of stroke or an insight stemming from 



ted warmth of tumors. What we found in their stories was defiance. 



? the tenets of their time, they have proved that it's indeed the thought that counts. 



o 

I— 

< 

Q_ 

z 



o 

to 

< 

00 



Ernest Darkoh defies 

the skeptics and helps 

a nation save itself. 

Eye of 
the storm 



hy Ann Marie Menting 




OTSWANA HAD LARGELY ESCAPED 



the HIV epidemic that rampaged through Africa 
during the 1980s. A peaceful republic with immense 
diamond wealth, the nation had prospered since its 
independence in 1966, achieving high rates of litera- 
cy and immunization and life expectancies that 



7. 




averaged 68 years. The nation's idyllic 
days were shattered in the early 1990s, 
however, when HIV invaded. Soon, 
Botswana's achievements were in tatters. 
By 2000, nearly 39 percent of the 
country's adults were infected with HIV. 
With families in mourning, children 
orphaned, and the country's core work- 
ing population dying on average before 
the age of 40, Botswana was, according 



20 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



^ 



NAiV\E: ERNEST DARKOH 
TENET CHALLENGED: 

HIV treatments in Africa are 
impossible because of costs, 
logistics, and the stigma 
associated with AIDS. 
SPARK OF INSPIRATION: 
The limitations of health care 
delivery systems in Africa — 
which contributed to the early 
death of a friend — outraged him 
and fueled his sense of mission. 



^ 



\ 



\ 





to its president, Festus Mogae, being 
"threatened with extinction." 

It was into this crisis that Ernest 
Darkoh '98 stepped when he arrived in 
Botswana in 2001. Part of a team 
charged with assessing the country's 
chances of mitigating its AIDS epidem- 
ic by providing free antiretrovirals to 
all in need, the assignment was, for 
him, a perfect match. 



Darkoh was born in the United States 
of Ghanaian academics. As a child, he 
moved to East Africa with his parents, 
who held professorships in Tanzania, and, 
later, Kenya. The toU that crime, poverty, 
and rickety health care systems took on 
the people of those nations troubled 
the young Darkoh. Inefficiency touched 
everyone; his own parents often had to 
wait for paychecks caught in bureaucratic 




tangles. So did sorrow; when Darkoh was 
19, a friend died because local hospitals 
refused him treatment, fearing he had 
AIDS. "His death," says Darkoh, "ignited a 
sense of outrage in me." 

Darkoh returned to the United States 
for his college education. After earning 
degrees in chemistry, biochemistry, and 
molecular biology at the University of 
Wisconsin and medical and public 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



21 



jm^^ 




health degrees at Harvard, he pursued a 
master's degree in business administra- 
tion from Oxford. The blend satisfied his 
desire to enhance his health care training 
with solid business principles so as to 
better meet the demands of the develop- 
ing world. It also provided him the agili- 
ty he would need to confront the devas- 
tation of AIDS to an African nation — and 
to counter skeptics who viewed his 
work as a hopeless endeavor. 

Dawn's Early Light 

Botswana's president wanted to answer 
the epidemic's assault quickly and deci- 
sively. At this same time, representa- 
tives from the drug giant Merck and its 
corporate foundation and from the 
Bill &r Melinda Gates Foundation were 
looking for a country with which they 
could join forces and implement a com- 
prehensive program that would fight 
the spread of HIV. The three groups 



formed a partnership with the govern- 
ment of Botswana and ACHAP, the 
African Comprehensive HIV/AIDS Part- 
nerships, was born. This new group pro- 
vided the impetus the African nation 
was seeking. 

To Darkoh, this collaboration repre- 
sented, "a fortunate coincidence of pur- 
poses and intent." ACHAP arranged for 
Darkoh and the team, all from the man- 
agement-consulting firm McKinsey &r 
Company, to join with Botswana's Min- 
istry of Health in determining what it 
would take to establish a national anti- 
retroviral program. 

The McKinsey team found that more 
than one-third of the approximately 
300,000 HIV-infected people in Botswana 
needed antiretroviral therapy immedi- 
ately. The team also devised strategies 
for ramping up the nation's infrastruc- 
ture and for identifying areas in which 
capacity and capability needed to be 
strengthened or developed, including 



communication and education pro- 
grams, training programs for health care 
providers, and a system for tracking and 
monitoring patients, laboratory sam- 
ples, and medication use. 

Botswana's national treatment pro- 
gram was launched in January 2002, 
and the program, called Masa — meaning 
"new dawn" in Setswana — was estab- 
lished. Impressed by Darkoh's work, 
ACHAP and Botswana's Ministry of 
Health asked him to head up Masa. He 
jumped at the opportunity — and into a 
job with monumental demands. 

"It was uncharted territory," says 
Darkoh. "In epidemiological terms, a dis- 
ease that affects 1 percent of a population 
is a catastrophe. With almost 40 percent 
of its adult population infected with 
HIV, Botswana faced a cataclysmic situa- 
tion. As much as anything, we needed to 
bring hope to people who felt hopeless." 

Within 15 months, the program had 
enrolled 6,000 patients at four treatment 



22 



HARVARD MEDICAL ALUMNI BULLETIN -AUTUMN 2006 



to see the change in attitude. 
People understand that regardless of their HIV status, 
they have viable options that allow them to live full lives." 



centers; more than 3,000 patients visited 
one clinic alone to receive antiretroviral 
therapy. A year later, the program had 
quadrupled the number of patients 
receiving antiretroviral therapy and had 
increased the number of clinics to an 
even dozen. Botswana was soon reaching 
16 percent of its people who needed anti- 
retrovirals, the greatest outreach achieved 
at that time by an African country. By 
November 2004, the program had 34,000 
patients on antiretrovirals, a figure that 
represented 9 percent of all people receiv- 
ing such therapy worldwide. Botswana is 
now providing treatment to more than 
70 percent of those in need. 

The pace set in the program's first two 
years left Darkoh little time to rest. He 
juggled the logistics of setting up new 
clinics and laboratories, developing a 
nationwide tracking system for patients, 
and ensuring a steady supply of trained 
care providers in cities, towns, and vil- 
lages. And he put out fires sparked by the 
sheer heat of the program's progress. 

"It was a sprint every day," says Darkoh. 
"Although the program's roll-out was 
phased, we had to move fast. We couldn't 
allow the early clinic sites to become 
overwhelmed with demand, and we had 
to ensure that people everywhere could 
get to a chnic easHy, without traveling 
long distances. So once we knew the 
teething problems that pilot sites faced, 
we made adjustments to minimize those 
problems and quickly set up new sites." 

"I also kept pushing to get more people 
tested," Darkoh says. "I knew it was 
imperative that we started treating 
people before they became very sick. The 
only way to do that was to determine who 
was ehgible for antiretroviral therapy." 

"We also hoped to make a different 
type of citizen," adds Darkoh, "to empow- 
er people by providing them the infor- 
mation they needed to make behavioral 
choices. Why should a billboard pro- 
moting condom use interest you when 



you don't know your HIV status? We 
needed to make it personal." 

Darkoh's wish became a reality when 
Botswana changed to an "opt-out" test- 
ing system. Previously, the country had 
followed the practice used in most places: 
Patients visitiQg a clinic would be coun- 
seled on HIV and then given the choice of 
being tested for the virus. Such "opt-in" 
approaches usually yielded few takers. In 
making the check for HIV part of the 
standard laboratory battery of tests 
patients received at chnics, Botswana did 
more than just increase the number of 
people who were tested for HIV — it also 
defused some of the stigma associated 
with the test, a crucial aspect for mem- 
bers of such a tightly knit population. 

Having people learn their HIV status 
helped expand the pool of individuals 
eligible for antiretroviral therapy — and 
lengthen the queues at Masa's clinics. 
Aside from adding to wait times, long 
queues meant that less critical patients 
often had to step aside to allow those 
with severe symptoms to receive atten- 
tion. Too many steps out of line meant 
fewer opportunities to have therapy 
monitored, a prescription that, over time, 
only added to the ranks of those who 
were severely lU. 

To solve this dilemma, Darkoh split 
the lines, and, analogous to checkouts in 
groceries, estabhshed queues for patients 
with fewer needs and queues for patients 
with many needs. By identifying days 
and times for clinic visits by specific 
patient populations, this strategy 
increased the number of patients seen in 
any one clinic, and, more important, 
allowed patients who were not desper- 
ately ill to be monitored regularly. 

Global Operations 

The Masa program continues to add to 
the numbers of people being tested and 
treated. And with more than 30 sites up 



and running, the program has estab- 
lished treatment centers at every refer- 
ral, district, and primary hospital in the 
country. Adherence to treatment regi- 
mens has proven to be solid, as evi- 
denced by self-reports, attendance at 
scheduled appointments, and measures 
of viral suppression among patients. 
Best of all, the nation's mood has shifted 
from despair to hope. 

"It is heartening to see the change in 
attitude," says Darkoh. "People under- 
stand that regardless of their HIV status, 
they have \dable options that allow them 
to continue to seek — and live — full hves." 

The program's success has also caused 
skeptics — ^who had believed any attempt 
to deliver HIV treatments to people in 
Africa were doomed from the start — to 
fall silent. Those fighting the epidemic 
in other African nations are now tele- 
phoning Darkoh to ask how the Masa 
program could work in their country. 
Although he is no longer in charge of the 
program, having helped transfer it to 
local management, Darkoh welcomes the 
calls. In fact, he recently joined with two 
colleagues to form BroadReach Health- 
care, a company that designs health care 
dehvery and treatment programs that 
can quickly be scaled up from concept 
to country-sized. 

Although satisfied with his accom- 
plishments in Botswana, Darkoh is 
clearly aiming for a time when the 
model he honed in that country multi- 
plies into multinational, multi-disease 
programs that operate with the effi- 
ciency of the best business practices 
and the sustainability of a long-lived 
organism. UntU then, one country at a 
time, he's perfecting his scalability 
model, ensuring it is nimble and fit, 
capable of meeting the demands any 
epidemic may throw at it. ■ 

Ann Mark Mcnting is associate editor of the 
Harvard Medical Alumni Bulletin 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



NAME: JOAN BRUGGE 
CHALLENGE TACKLED: 

Learning how a cell becomes 
cancerous requires an under- 
standing of the intricate 
pathways and mechanisms 
that govern its behavior. 
SPARK OF INSPIRATION: 
She crafted an innovative 
model of breast epithelial cells 
that can be used to decipher 
how genes and their proteins 
drive the cancer process, 
providing clues that may one 
day help explain a disease 
that took her sister's life. 







Joan Brugge chips 

away at the secrets 

of a disease that 

claimed her sister. 




corps 



hy Ann Marie Menting 



IVE JOAN BRUGGE A 

problem to solve and she's good to go. It's a skill she 
developed early. Passionate about mathematics, she 
formulated her career plans while still in high school: 
a degree in the field followed by a career educating 
future generations to the beauty and satisfaction 



found in unraveling problems and knit- 
ting their solutions. 

Then Me presented Brugge with an 
unsolvable problem, one not of formulas 
but of family. Her sister Mary Pat was 
diagnosed with a brain tumor. Brugge, 
accustomed to teasing forth answers to 
tough questions, found herself confront- 
ed with impenetrable ones; what had 
caused the tumor, and how could her sis- 
ter's life be saved? But aside from a stray 



comment from her sister's neurosurgeon 
that one day viruses would hkely be 
found to play a significant role in carcino- 
genesis, her inquiries were met by silence. 
With a clarity sharpened by grief over 
her sister's death, Brugge recast her 
future. Solving problems would stiU be 
central to it, but now those problems 
would be microscopic, not mathematic. 
Brugge revamped her college studies, 
adopting biology as her major and taking 



on an independent study of viruses and 
oncogenesis. A summer laboratory intern- 
ship introduced her to research, and she 
was captivated: "The small project I was 
responsible for introduced me to the sci- 
entific process and gave me a sense of the 
thrill that scientists experience when 
they explore uncharted paths. I became 
consumed by the need to do research." 

For more than 30 years, Brugge has 
been busy charting some of those paths 
through her investigations of genes and 
proteins, especially of the ways in which 
their activities contribute to cellular 
behavior, both healthy and aberrant. 

Sniffing Out tfie Truth 

Since stepping into the world of scientific 
discovery, Brugge has never been tempted 
to look back. She has often taken great 
dehght, however, in looking sideways. 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 25 



i\ 8 V ^OiiCclgUCvS and I were like bloodhounds 
t following the scent, hoping to be led to where the 

orotein was produced and where it was expressed." 



"I followed one protein for most of my 
early career," says Brugge. "It was a long 
search to understand its function in nor- 
mal cells and then to understand how per- 
mutations of that function could cause a 
normal cell to turn cancerous. The search 
took me in totally unexpected directions, 
ones far afield from cancer. But each 
detour gave me insights into the nature of 
the pathways that the protein controlled." 

The protein that Brugge tracked — 
pp60^''®'^'^ — is one produced by both the 
cellular and viral forms of the src gene. 
Brugge had isolated the protein while 
working as a postdoctoral fellow in the 
laboratory of Ray Erikson at the Univer- 
sity of Colorado in the late 1970s. Their 
discovery of what is now called v-Src 
rocked the field of cell biology; they had 
found what many held to be the holy grail 
of oncogenesis. 

The isolated protein turned out to be 
an enzyme that transferred molecular 
groups called phosphates from a cell's 
energy source to other proteins. Scien- 
tists learned that such phosphorylations 
regulate how a cell proliferates, becomes 
invasive, and even survives. In her own 
laboratory, Brugge began to zero in on 
how the protein regulated normal cellu- 
lar processes. 

"My colleagues and I were like blood- 
hounds following the scent, hoping to be 
led to where the protein was produced 
and where it was expressed," says 
Brugge. "Our studies pushed us to inves- 
tigate neurobiology, platelet biology, cel- 
lular adhesion, and intracellular signal- 
ing pathways." 

Her peripatetic investigations were 
also pushing Brugge to consider new 
research opportunities. In 1992, she left 
academia to become the scientific direc- 
tor of ARIAD Pharmaceuticals, a Cam- 
bridge, Massachusetts-based biotech- 
nology start-up. There Brugge planned 
to expand her investigations of the sig- 
naling pathways that dictate the disease 



process and to begin investigations of 
how cells respond to signals from pro- 
teins in their environment, a process 
known as signal transduction. 

For five years, Brugge conducted her 
research while juggling the administra- 
tive and travel demands of the fledgling 
company. Although the research thrilled 
her, she was dogged by the knowledge 
that her laboratory time was too curtailed 
to allow her to do investigations that met 
her own high standards. In addition, 
Brugge was again pondering a new hne of 
inquiry, one that would, she hoped, pro- 
duce an in-vitro model that closely reph- 
cated how cells organize themselves in 
living tissue. So, in 1997, with a track 
record of stellar research in hand and 
innovative investigations in mind, Brugge 
accepted a professorship in the Depart- 
ment of Cell Biology at HMS; in 2004, she 
became the department's chair. 

A Bad Influence 



In the field of oncogenesis, researchers 
have largely rehed on fibroblasts to study 
cancer development within the laborato- 
ry confines of a Petri dish. The reasons are 
practical; connective tissue cells are easy 
to culture and to render immortal, thus 
allowing scientists to monitor changes 
in cellular development and function 
through umpteen generations. 

Most human tumors, however, origi- 
nate in epithelial tissue. So instead of 
clinging to the established paradigm, 
Brugge fashioned an in-vitro model 
using breast epithelial cells. She knew 
epithelial cells behave quite differently 
when allowed to organize into struc- 
tures that resemble those they form in 
living tissue. When so organized, these 
cells function as they do in the body. 
Salivary cells, for example, will produce 
saliva, and breast cells wHl produce 
milk. Growing epithelial cells in Petri 
dishes was unnatural; the rigid surfaces 



could not mimic the elastic structures 
of the body. 

Brugge's model drew upon pioneering 
work using extracellular matrix pro- 
teins. First, she filled pea-sized chambers 
with a gel enriched with such proteins as 
coUagen and laminin. Then she suspend- 
ed breast epithelial cells in the gel. Her 
model worked beautifully. The cells 
organized into three-dimensional struc- 
tures that resembled the rrulk glands of 
human breast tissue — cellular spheres 
whose hollow centers are kept clear by a 
surveillance system that gives any infil- 
trating cell a greeting so brutal that the 
wayward cell initiates the death process 
known as apoptosis. 

With a viable model developed, Brugge 
could now better track the pathways and 
mechanisms that change normal breast 
cells into cells that proliferate excessively, 
migrate into tissue that is not their turf, 
and become so robust that they can fend 
off the body's messages to cease and desist. 
In short, Brugge wanted to reconstruct 
the disease process one gene at a time. 

"We set up a series of experiments to 
identify the genes involved in breast 
cancer and to try to fit those genes into 
known pathways regulated by growth 
factors and adhesion receptors," Brugge 
says. "Our screens using HER2 showed 
us the power of this model." 

The HER2 gene is found in the 
genomes of breast cancer cells, particu- 
larly those forming a noninvasive type of 
cancer called ductal carcinoma in situ. In 
cells with this gene, DNA duphcation 
often goes awry: It gets caught in a loop, 
repeatedly duplicating the sections of the 
chromosome that contain HER2. Such 
duphcation can increase the cell's HER2 
presence by 25- to 30-fold, an amplifica- 
tion that brings with it an overproduc- 
tion of the protein produced by the gene 
and, consequently, a barrage of the signal 
that protein is responsible for gi^Tng the 
cell. Unregulated growth results, and a 



26 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 




tumor forms. "It's like hitting the gas 
pedal," says Brugge. "Cellular rephcation 
goes out of control." 

Although it is possible to target 
HER2 therapeutically, the cells can 
become drug resistant. Brugge thought 
a stronger approach might be to home 
in on the pathways and mechanisms by 
which the gene and its protein acted. 
This would, she reasoned, provide a 
more universal understanding of the 
cancer process as it would highlight the 
cellular missteps central to the forma- 
tion of any type of tumor. 

Brugge and her research team intro- 
duced HER2 into the model system and 
waited. The results were eye openers: 
The cells not only proliferated madly, 
but the structures they formed had cells 
in the normally empty interiors of the 
spheres. Signals from HER2 proteins, 
therefore, exercised a double whammy; 
they caused hyperproliferation and they 
turned off the structure's sentinel sys- 
tem, allowing the proliferating cells to 
live when they should have died. In 
addition, the group found that when 
cells with amplified HER2 also con- 
tained a certain growth factor, they 
became capable of metastasizing. 

"It was striking," says Brugge, "how 
closely the architecture of the cultured 



structures resembled the architectures of 
the different types of tumors found in vivo." 
The model system could rephcate the 
disease process — at least as undertaken 
by one cancer-related gene. Brugge was 
now ready to define the roles of other 
genes implicated in breast cancer. 

Check It Out 



This year, Brugge, together with Joshua 
LaBaer, director of Harvard's Institute of 
Proteomics, established the Breast Can- 
cer 1000 initiative — the first public 
library of proteins that are reliably 
expressed in breast cancer. Containing 
1,300 complementary DNA, stable forms 
of the molecule that are capable of pro- 
ducing the sought-after proteins, the 
hbrary will allow researchers to interpret 
the choreography of cancer. Is, for exam- 
ple, a particular protein that is altered in 
a breast tumor cell a principal player in 
the disease process or a victim of it? How 
does a protein contribute to the diseased 
cell's ability to invade, grow, or change 
how it relates to its environment? 

To evaluate the range and functionaUty 
of the hbrary, Brugge and her team insert- 
ed into the model system nearly 300 com- 
plementary DNA whose roles in the dis- 
ease process were already known. Each 



was then subjected to a series of screens 
that identified how the DNA's protein 
product contributed to the disease 
process. Their screens not only vahdated 
the system as a testing mechanism but 
also uncovered some genes not yet known 
to play a part in the disease's biology. 

With studies of proteins and the can- 
cer process well under way, Brugge has 
begun looking at what happens higher 
up the cellular ladder, at the genomic 
level and, ultimately, at a systems, or 
whole body, level. It is unlikely her search 
for answers will diminish or her list of 
questions shorten. The college student 
who looked to others to make sense of 
her sister's illness now knows that, 
through her own research, she can cut 
windows into the darkest of black boxes. 

"I'm enjoying the research I'm now 
doing more than any science I've done," 
Brugge says. "I'm addicted to discovery, 
to being presented with an unanswered 
question, pulling together the informa- 
tion needed to build a hypothesis, 
designing an experiment to test that 
hypothesis, and then interpreting the 
results. It's what drives me — the explo- 
ration of the unknown." ■ 

Ann Marie Mcnting is associate editor of the 
Harvard Medical Alumni Bulletin. 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 27 



The thin 



hy Pat McCaffrey 




red hne 



udah Folkman 
devotes decades 
to proving an 
unpopular theory. 



UDAH FOLKMAN '57 GOT HIS FIRST LOOK AT 

cancer in its natural habitat when he was removing 
tumors from patients in the late 1950s. Folkman is now 
the Julia Dyckman Andrus Professor of Pediatric 
Surgery at Harvard Medical School, but back then he 
was a surgical resident at Massachusetts General Hospital. 



The malignancies he routinely encoun- 
tered in the operating room bore little 
resemblance to the neat slices of tissue 
he'd studied mounted on microscope 
slides, or the flat bed of cells growing 
in Petri dishes in the research labora- 
tory. Actual tumors, he realized, were 
a bloody mess. 

During an operation, Folkman could 
feel the heat — like that of a child's 
fever — from a large mass. He saw hun- 



dreds of blood vessels, some coming 
from great distances to supply the 
malignancy. Indeed, he spent hours in 
the operating room carefully cauterizing 
each small bleeder before finally remov- 
ing the tumor, all in an effort to prevent 
dangerous blood loss. 

After his residency, Folkman was 
drafted and assigned to the Naval Med- 
ical Research Institute in Bethesda for 
two years. There he implanted cancer 



cells into isolated rabbit and dog thyroid 
glands. Tiny tumors appeared, but then 
stopped expanding at a size smaller than 
the diameter of a pencil point. Yet when 
he transplanted these tiny white tumors 
into mice, the tumors rapidly grew to the 
size of a marble and reddened. What, he 
wondered, was the difference? 

It turned out the answer had been 
right in front of him, on the operating 
table. Tumors, he realized, were like 
any other tissue in the body. They need- 
ed a robust blood supply to grow and 
thrive. Without that, they might stay 
small and sometimes even disappear. 
What if, Folkman thought, the secret of 
these large tumors' success depended 
on their forming their own new blood 
supply? What if the cancer cells pro- 
duced factors that drove the produc- 
tion of blood vessels and the blood ves- 
sels fed the tumor? 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



■'■\ 




(j^^^olkman 



/ 







/ 





X. 




A 



HT 





NAME: JUDAH FOLKMAN 
NEW TENET OFFERED: 

Tumors spur the development 
of their own blood vessels, a 
process called cngiogenesis. 
SPARK OF INSPIRATION: 

The warmth of tumors made him 
wonder whether they, like the 
other tissues in the body, needed 
their own blood supply — and 
whether they could be starved 
if that blood supply was cut off. 



I 



' ^ V*^ 



^ 



' -"i'S^ 



A 



His dual experience in the operating 
room and in the laboratory led Folkman 
in 1971 to propose this new theory of 
tumor angiogenesis, a word meaning the 
assembly of new blood vessels. In an 
article that year in the New England 
Journal ojMcdicinc, he introduced his idea 
that tumors might control vessel growth, 
and vice versa. An important corollary to 
that idea was that if researchers could 
find the means to stop the blood supply, 
then the cancer should likewise halt. 
He coined the term "anti-angiogenic 
therapy" and forecast that one day 
angiogenesis inhibitors would be used 
to treat cancer. 

All of this turned out to be true — 
although it took three decades to prove 
it. His 1971 article, which at first gained 
httle notice, is now viewed as the semi- 
nal publication in a large and growing 
field of research. On the clinical side, 
eight different angiogenesis inhibitors 
are now on the market to treat a variety 
of cancers. At least 30 more are in human 
trials, aiming for Food and Drug Admin- 
istration approval. 

Moreover, cancer is not the only dis- 
ease in which the use of angiogenesis 
inhibitors has made a difference. These 
blood vessel blockers are the newest and 
most effective treatment ever for age- 
related macular degeneration, the lead- 
ing cause of blindness in people over 65. 
The condition causes sight loss when 
blood vessels infiltrate the retina, cloud 
it, and eventually destroy it. In a recent 
clinical trial, treatment with an angio- 
genesis inhibitor stopped the disease 
in 95 percent of patients. Amazingly, it 
restored vision in four out of ten treated, 
to the point at which legally blind people 
regained enough eyesight to drive a car. 

A recent editorial in the normally 
understated New England journal of Medi- 
cine, coming 35 years after Folkman's 
original proposition, called the treat- 
ment "miraculous." 




Doubt Yields to Data 

Ironically, the surgeon's skill contributed 
to the early and persistent doubts among 
other researchers that cancers could grow 
their own blood supply. That's because 
a properly excised tumor looks entirely 
different from how it first appeared to the 
doctor. With the vessels painstakingly 
sealed off, the prexiously engorged tissue 
is drained of blood, its \'essels collapsed. 
The idea that tumors could be magnets 
for blood vessel growth didn't jibe with 
the cold, white lump that the patholo- 
gists found deposited in their sample 
pans outside the operating room door. 

"People thought I was crazy," Folkman 
says. "And some pathologists were very 
critical. But they didn't see what I saw in 
the operating room. Back then, no one — 
including my colleagues at Harvard — 
beheved that tumors needed new vessels. 
They thought cancers would get along fine 
on the existing vessels. That red color, they 
said, was inflammation from dying tumor 
cells. They didn't believe tumors made a 
specffic protein to regulate vessel growth. 
Anyway, they said, they knew of no mole- 
cules that could make blood vessels grow." 

AU of the objections to the idea of angio- 
genesis were beliefs, Folkman says, and 
when scientists hold to beliefs, it takes data 



1)^ 




goDon^ 



to change their minds. Those data began 
to accrue a few years later, when Folkman 
and his postdoctoral fellow Robert Langer, 
now a professor at HMS and MIT, demon- 
strated that a protein purified from tumor 
cells could coax blood vessels to grow. 
The assay they developed, which has since 
become the gold standard for measuring 
tumor angiogenesis, im'oh'ed placing a 
few tumor cells in a pocket of a rabbit's 
eye tissue. The cells would sit, growdng 
slowly, until after a few weeks blood ves- 
sels would begin to snake out over the eye, 
heading for the tumor. Once the blood 
supply reached the cancer cells, tumor 
growth exploded. Simply by looking at 
the eye, Folkman and Langer could teU 
that the tumor was producing an angio- 
genic factor, which they set out to isolate. 

In one key experiment, the researchers 
replaced the tumor with the protein fac- 
tor extracted from cancer cells. To do 
this, they had to inx'ent a way to package 
the protein in a sustained-release depot. 
Langer did that, and to the researchers' 
dehght the blood vessels read the depot 
as a tumor and began to grow toward it. 

More exciting than that, says Folk- 
man, was what happened when they let 
the blood supply develop and then 
removed the depot. Within a few weeks, 
the blood vessels disappeared. 



30 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



relieved that tumors needed new vessels. They thought cancers 
would get along fine on the existing vessels." 



"That was a big moment," Folkman 
remembers. "When we saw that the con- 
stant presence of the protein factor was 
needed to maintain those vessels, we knew 
our idea was right. We knew that, in theo- 
ry, an angiogenesis inhibitor could work to 
cut off the blood supply to tumors. From 
then on, it didn't matter what the critics 
said. I knew they were wrong." 

The next decade brought ups and 
downs in the laboratory. In 1994, another 
postdoctoral fellow identified the first 
angiogenesis inhibitor made by cells 
themselves, a protein the researchers 
dubbed "angiostatin." When the labo- 
ratory showed that a relative of angio- 
statin, called endostatin, prevented 
tumor metastasis in mice, the race was 
on to launch the recombinant protein 
into clinical trials for cancer. In those tri- 
als it appeared that endostatin had failed, 
because even though tumors and their 
metastases remained stable with arrest- 
ed growth for up to three and a half years 
in some patients — and the patients 
remained active and without side 
effects — the tumors did not regress and 
so were graded as "no response." 

Other kinds of inhibitors quickly 
replaced endostatin. Many of the current 
and- angiogenic drugs are antibodies and 
small molecules that mimic, at least in 
part, endostatin action. Recently a new 
version of endostatin proved effective 
and is now in use in China, a develop- 
ment Folkman hopes will be replicated 
in the United States. 

The Next Big Thing? 

Today, the Folkman domain encompass- 
es 80 researchers in 15 affiliated labora- 
tories on the top two floors of the Karp 
Family Research Laboratories of Chil- 
dren's Hospital Boston. Around one 
conference room, framed enlargements 
of the covers of research journals chron- 
icle the fits and starts of their progress. 



When his ideas were less popular. Folk- 
man hung up the first covers featuring 
their work to encourage his researchers 
to plod on. Now, the walls are blanket- 
ed with more than 30 reproductions, 
each documenting one eureka moment 
after another. 

In the conference room one floor above 
hang the many prizes Folkman has 
received for his work. Arrayed on the 
walls are dozens of plaques and framed 
certificates from organizations, govern- 
ments, and universities all over the world. 
Folkman proudly points out one of the 
latest — the Helen Keller Prize for Vision 
Research, in honor of his group's work on 
new treatments for macular degeneration. 

At 73, Folkman still has the surgeon in 
him. He roams the lab in a clean white 
coat with his name stitched in red let- 
ters over the breast pocket. Underneath 
he wears a pressed shirt and necktie. 
He has passed the age at which many 
researchers retire, but that is a move he 
is not contemplating. 

"When Verdi was in his seventies," 
Folkman says, "people asked him what 
his best opera was, and he answered, 'I 
haven't written it yet.' When he was 
close to eighty, he wrote Falstaff. For 
me, the ideas keep coming, and maybe 
because of experience, they're better and 
better. As long as these kinds of ideas 
are coming and we're working on them, 
I should keep on going." Those words 
might seem boastful, but Folkmaris soft 
voice lends them a more modest tone. 

His latest project is finding ways to 
treat cancer before it becomes a surgeon's 
problem. Recent work has revealed that 
we aU carry microscopic tumors through- 
out our bodies, but only one tumor in a 
thousand turns into a cancer that is diag- 
nosed and requires treatment. Folkman 
showed that all the others stay small 
because they are not angiogenic. Once 
the tumors switch on blood vessel 
growth, though, the cancer grows rapid- 



ly, and symptoms appear. If a doctor 
could teU by a blood test that the angio- 
genic switch has ffrpped, Folkman theo- 
rizes that the patient could then be treat- 
ed immediately with anti-angiogenic med- 
icine, and the tumor would wither. 

Folkman makes an analogy to the 
treatment of infections before antibi- 
otics. "There were no drugs for infec- 
tions, only surgeons. If you had an 
abscess, the surgeon would find it and 
drain it. Now, we rarely need to do that. 
If we have a patient with an infection, 
we don't do a CAT scan or an MRI to 
localize it. We just look at the blood 
count and treat." 

He'd like to do the same for recurrent 
cancer. "If we had a really good bio- 
marker — a sentinel protein in the blood, 
for example — ^we could conceivably use 
the biomarker as a guide in our treatment 
of recurrent cancer or for diagnosing a 
nascent cancer before it manifests symp- 
toms. Such indicators could also help us 
design more effective treatments by 
detecting a tumor before it is anatomical- 
ly visible or by showing us that a patient's 
anticancer drugs have lost their punch. 

"Now I know today that few people 
believe that. They say you can't treat a 
tumor you can't see, or you can't treat a 
patient who has no symptoms." 

Yet Folkman and his colleagues are 
trying this very approach for the first time 
with a patient at risk for recurrence of 
tumors. "If and when we get our results," 
Folkman says, "we'll pubHsh them. It may 
be a unique case of treating cancer guided 
only by a biomarker in the blood, without 
actually seeing the recurrent tumor." 

"And no one will believe it," he says 
with a laugh. "But after the hundredth 
patient, they may. And after that, my guess 
is that such treatment could become a 
common occurrence." ■ 

Pat McCaffrey is a freelance writer based in 
Auhurndalc, Massachusetts. 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



31 



Jim Yong Kim advocates 
for change in the moral 
debate over treatment. 



The Dossible 







dream 



hy Ann Marie Menting 



RINGING HEALTH CARE TO THE 



poor living in the farthest corners of countries, in 
urban angles and alleys, and in the difficult spots in 
between is not only feasible, it's the only fair thing to 
do, insists Jim Yong Kim '91. ■ Kim is an idealist, an 
advocate who, whether working among the poor in 



resource-scarce countries or among 
the powerful in the halls of the world's 
leading health organization, has but one 
goal: health care for all. 

"When I was at Harvard, I heard an old 
aphorism that students entering medical 
school are among the most ideahstic of all 
students," says Kim, "but they're among 
the least ideahstic by the time they leave." 

Kim's career has given lie to that 
adage. Throughout medical school, he 



32 HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



held onto his global care ideal so firmly 
that he capped his degree with a doctor- 
ate in medical anthropology. "I wanted 
to figure out how could I push forward a 
process that would provide health care 
to everyone," says Kim. "That question 
has stayed with me." 

To listen to Kim, it is easy to hear the 
strength of his passion for health care 
equahty and to discern the skill he has 
shown in channeling that passion into 



programs to dispel care disparities. It 
does not take much to realize this 
unabashed ideahst has been quietly com- 
posing a health care pohcy revolution. 

Field Day 

Kim started putting his ideals into prac- 
tice while still a student at HMS. In 1987, 
he connected with Paul Farmer '90, 
another HMS student-idealist con- 
sumed by the same goal. Kim joined 
Farmer in the newly launched Partners 
In Health (PIH), a Cambridge, Massa- 
chusetts-based nonprofit dedicated to 
supporting health care programs for the 
poor in Haiti, especially those hving with 
HIV. Together the young physicians built 
the organization, and, in 1994, at the urg- 
ing of Father Jack Roussen, a long-time 
PIH supporter, expanded it to include 
treatment programs for people living 



'^NAME: JIM YONG'^ 
CHALLENGE TACKLED: 

People in developing countrie| 
were dying of mulfidrug-resistc 
tuberculosis — and the complex 
treatments that could save them 
seemed out of reach. 
SPARK OF INSPIRATION: 
He convinced generics 
manufacturers to moke off- 
patent drugs available at a 
fraction of their original cost. 




^ 






with tuberculosis in Carabayllo, 
a shantytown on the fringes of 
Lima, Peru. 

In Peru, Kim and Farmer were 
decried as medicos aventurcros — 
medical adventurers — by some 
and dismissed as Harvard "egg- 
head" researchers by others, 
but were lauded as health care 
advocates by most. The situa- 
tion they faced in Carabayllo 
would demand the fearlessness 
implied by those monikers. 

At that time, tuberculosis 
was rampant among Peru's poor. 
The standard treatment for the 
disease was failing a significant 
number of patients; officials in 
the health ministry accused the 
patients of neglecting to take all 
their medications. The conse- 
quences of inadequate compli- 
ance are grim: Such an environ- 
ment would allow the tuber- 
culosis bacterium to develop 
resistance to the drugs used in standard 
therapy. And then Roussen fell ill. 

The PIH team flew the priest to 
Boston for treatment, where they found 
out — too late — that the bacteria causing 
Rousserfs iUness were resistant to every 
first-line tuberculosis drug. The priest's 
death not only saddened Kim, it dis- 
mayed him as well: Roussen had not been 
treated for tuberculosis before he fell ill, 
so an improper use of medications could 
not have contributed to his resistance. 

Kim realized that drug-resistant forms 
of tuberculosis were thriving among 
Peru's poor; first-line medications were 
no longer effective. For people who were 
contracting multidrug-resistant tubercu- 
losis (MDR-TB), standard therapy, even 
when well followed, would always fail. 
New therapies were needed. 

Providing treatments for MDR-TB 
would be expensive, but Kim and Farmer 
were convinced it was possible to devel- 




op and implement complex interven- 
tions that could treat the MDR-TB epi- 
demic sweeping through Peru's poor. 
The trick, as they saw it, would be con- 
vincing others. 

"We needed to shift the moral debate," 
says Kim. "We saw the MDR-TB scourge 
as the way to do this. It's a communicable 
disease, and we're all hving in one world. 
It was a disease that actually scared 
wealthy people. So we kept pushing and 
kept getting press. Soon we had the ear 
of people who could help move forward 
our program to treat MDR-TB." 

PIH established community-based 
treatment programs to assist people 
with MDR-TB in Haiti and Peru and, 
later, in Russia. Building on the DOTS 
(Directly Observed Treatment Short- 
course) plan for treating tuberculosis, 
which had been embraced by the World 
Health Organization (WHO), Kim and 
Farmer devised a DOTS-Plus program 



that used both first- and second-line 
drugs to treat MDR-TB. One obstacle — 
getting the needed drugs cheaply — 
immediately loomed. But Kim, who had 
analyzed the Korean pharmaceutical 
industry while researching his disserta- 
tion, reahzed this was a problem that 
could be solved relatively easily. 

Kim knew that as a drug migrates 
from branded- compound status to that 
of off-patent generic, its sticker price 
nosedives, ultimately falling by as much 
as 95 percent. Kim succeeded in getting 
generics manufacturers to produce the 
needed drugs, which had been off patent 
for some time, and to sell them at I to 5 
percent of their open-market cost. Kim's 
trailblazing effort paid off for PIH — and 
others. More than 30 countries have since 
followed Kim's plan and acquired top- 
hne drugs at bargain-basement prices. 

The PIH MDR-TB program achieved 
an 85 percent cure rate in its first group 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



did not reach its goal of bringing 
treatment to three milhon people, it did succeed in getting treatment 
to nearly one million, a previously undreamed-of achievement. 



of patients in Peru, a rate that surpassed 
those of some of the best U.S. hospitals. 
The team's efforts among populations in 
Haiti and Russia also succeeded, as did a 
similarly structured HIV-treatment pro- 
gram PIH launched in Haiti. 

World Premiere 



To the PIH team, accumulating evidence 
of the feasibihty and efficacy of their 
community-based treatment programs 
meant they could move to what they con- 
sidered the next stage — changing inter- 
national health care policy governing 
infectious diseases. To do this, they need- 
ed to persuade policymakers to push 
for treatment programs for a troika of 
killers: malaria, tuberculosis, and HIV. 

The PIH team decided to open a second 
front. Farmer would stay in the field, con- 
tinuing to estabhsh the merits of novel 
treatment programs in resource-scarce 
settings, while Kim would take on the 
challenge of working for change in inter- 
national health care pohcy. It was a daunt- 
ing task, but one Kim was set to tackle. 

In 2004 Kim stepped onto the global 
stage, taking a sabbatical from his posi- 
tion as codirector of the HMS Program in 
Infectious Disease and Social Change and 
moving to a post as director of the 
WHO'S HIV/AIDS department. He 
arrived at the Geneva-based organiza- 
tion during its transition from one direc- 
tor general to another. It was in this envi- 
ronment of change that Kim set about 
agitating the institution's leaders to think 
on a scale large enough to take on the 
tasks demanded by global epidemics. 

"When I went to the WHO, I told the 
director general I wanted to do something 
revolutionary in HIV treatment," says 
Kim. "His predecessor had floated an idea 
for bringing HIV treatment to 3 miUion 
people by 2005 and I told him that I 
thought this was an initiative we should 
undertake. It would be a difficult target — 



perhaps even impossible — but I thought 
it was something we should embrace. 

"He asked whether we could make the 
target, and I said, 'I think we can. But it's 
more important that we take a stand and 
insist that we try' He gave me the okay and 
we went for it. Boy, did we get attacked." 

To make what became known as the 
3 by 5 Initiative a global mandate, Kim 
helped marshal support from the 192 
member nations of WHO's World Health 
Assembly and worked to get the endorse- 
ment of other groups that made up 
UNAIDS, the United Nations umbrella 
organization that oversees its HIV/AIDS 
programs. Kim was seeking resolve on the 
part of these global institutions, a plan 
that would set targets and make demands 
of countries, something with teeth in it, 
rather than what he considered the orga- 
nization's usual action — a poHte declara- 
tion of commitment with httle incentive 
for implementation. 

The entire UNAIDS family acted, sup- 
porting not only the effort to push 
nations to dehver antiretrovirals to half 
the people who needed help within two 
years' time but also to assess each coun- 
try's progress every six months. Kim soon 
found that people either loved or hated 
the idea; there were few shades of gray. 

"The donors were extremely unhappy 
because we hadn't asked whether they 
would pay for such an effort. Health min- 
isters in some nations hated it. They 
were angry because I would point to 
numbers to show which countries were 
failing to move on the plan. 

"But others celebrated the initiative — 
poor people, people with HIV/AIDS, and 
people who worked to help those with- 
out access to treatment. And the Cana- 
dians loved it — and gave us 80 million 
dollars, bless them." 

Although the program did not reach 
its goal of bringing treatment to three 
million people, it did succeed in getting 
treatment to nearly one million, a previ- 



ously undreamed-of achievement. Over- 
all, the 3 by 5 Initiative has been deemed 
a success, credited with raising the bar on 
global pubhc health initiatives, pushing 
organizations and countries to think big, 
act big, and fund big programs designed 
to fight diseases threatening to kill or 
incapacitate millions of people and hob- 
ble the progress of dozens of nations. 

In late 2005, Kim returned to Harvard, 
where he has since taken leadership 
roles as chair of the HMS Department 
of Social Medicine and as director of 
the Harvard School of Public Health's 
Frangois-Xavier Bagnoud Center for 
Health and Human Rights. 

"First-year medical students have told 
me they want to learn how to build suc- 
cessful intervention programs to a scale 
that makes them effective for entire coun- 
tries," says Kim. "We're trying to respond. 
I'd like Harvard Medical School to teach 
the science of implementation for health 
care programs not only in the developing 
world but also in this country." 

To this end, Kim is helping to develop 
coursework that melds entrepreneurial 
ideas and good business practices with 
the idealistic aims of providing health 
care to the world's poor. The effort, he 
says, will produce a program in global 
health effectiveness in which medical 
students can learn to build treatment 
programs that are infused with the fruits 
of medical research and clinical innova- 
tion: They will be taught the science of 
global health care implementation. 

By crafting a tool that can be used in 
the implementation of programs that 
will provide health care to all, Kim is 
doing more than just remaining true to 
his goals. He is swelling the chorus 
working for social justice, populating it 
with young physicians eager to put their 
ideals into practice. ■ 

Ann Marie Mcnting is associate editor of the 
Harvard Medical Alumni BuUetin. 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



35 



Second 



Carla Shatz 

rewrites some of 

science's most 

sacred scriptures. 





hy Pat McCaffrey 



F YOU ASK NEUROBIOLOGIST CARLA 

Shatz to replay the highlights of her career to date, this 
is what she won't mention: In 1976, she became the first 
woman to receive a doctorate in neurobiology from 
Harvard. She was one of the first two female junior 
faculty members hired in basic science at Stanford 



University School of Medicine, and the 
first woman to receive tenure there. In 
2000, Shatz became head of the neuro- 
biology department at Harvard Med- 
ical School, the first woman in the his- 
tory of the department to be its chair 
and only the second woman in the his- 
tory of the School to chair a basic sci- 
ence department. 

Shatz never expected to become a 
pioneer or a role model for women sci- 



entists, and those accomplishments 
aren't her real highlights, she would say. 
For her, the memorable moments have 
all happened away from the limelight. 
Above all else, Shatz says, she is a scien- 
tist. And for that reason, the most 
exciting moments of her career have 
invariably come in the laboratory. 
What's more, she'll tell you, each was 
all the more memorable for being com- 
pletely unexpected. 



"One of the most enjoyable and 
engrossing parts of life as a scientist is 
that the work resembles a big mystery 
story," Shatz says. "With each twist and 
turn you get surprises." 

Seeing Is Believing 

Shatz, the Nathan Marsh Pusey Profes- 
sor of Neurobiology at HMS, has made 
her mark in her chosen field with stud- 
ies of how the eye and the brain get 
properly connected during early life. 
She was the first to see waves of electri- 
cal activity carried by nerve cells undu- 
late across the retina during fetal devel- 
opment, as the eye tested and retested 
its connections to the visual processing 
regions in the brain. In effect, she says, 
she caught the neurons rehearsing for 
vision before birth — long before the eye 
ever sees the hght of day. 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



^WR*E: 




IE: CARLA SHAT 
.TENET CHALLENGED: 

rhe brain operates in isolation 
from the immune system, a state 
Icalled immune privilege. 
SPARK OF INSPIRATION: 

Having documented some of the 
surprises the brain still holds for 
scientists, she persevered when 
skeptics dismissed her findings 
that an immune system molecule 
helped regulate the ability of 
neurons to rewire. 



I 








As she went on to demonstrate, the 
coordinated, in-utero communication 
between the nerve cells in the eye and 
the visual centers of the brain organizes 
and strengthens the connections between 
neurons. The rehearsal stage simply pre- 
pares the cells for becoming hardwired 
into visual circuits, which happens later 
in response to hght. 

When Shatz made that discovery, she 
and her students were watching the 
activity of neurons in a cat retina under 
the microscope. They were not surprised 
to see the neurons firing away — they 
expected that — but they were aston- 
ished to find entire groups of neurons 
signaling in a coordinated pattern. 

"That was incredible," Shatz says. 
"Everyone who saw it just said. Wow. The 
waves of activity were completely unex- 
pected, and we couldn't beheve how beau- 
tiful they were. I still play the movie we 
made then, because so many people can't 
beheve it. And we didn't either, at first." 

What Shatz saw turned out to be a 
leap in our understanding of how com- 
munication between groups of ceUs can 
organize whole brain circuits. "CeUs that 
fire together, wire together," she says. 

"What's really neat is since we discov- 
ered those waves, researchers have found 
them all over the brain during develop- 
ment," Shatz says. "Spontaneous nerve 
activity was known to exist, but the 
discovery that neighboring neurons are 
all correlated and firing together turns 
out to be crucial for understanding the 
way connections get set up, remodeled, 
and rewired." 

Immune to Criticism 



The next big surprise came when Shatz 
decided to look for the proteins control- 
ling the wiring process in the fetal brain. 
To do that, she and her laboratory team 
analyzed patterns of gene expression 
in the brain tissue of cats and mice 



RVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



cell Die Everyone who saw it just 
said, Wow. The waves of activity were completely unexpected, 
and we couldrit believe how beautiful they were." 



during normal development as well as 
when nerve signaling in the visual sys- 
tem had been blocked with a toxin. 

The gene that fell into their net was a 
stunner. As with the neuronal waves, it 
was at first hard to believe. What showed 
up in the remodeling neurons was a pro- 
tein belonging to the major histocompati- 
bility complex (MHC) class I family of 
molecules, the cell-surface proteins that 
help the immune system recognize foreign 
substances. Proteins produced by the 
cell's MHC gene cluster are best known 
for their role in the rejection of transplant- 
ed tissue. Cells aU over the body use MHC 
proteins — ^but they had never been found 
ki the nervous system before. 

The researchers wrote up the results, 
but their paper was rejected immediate- 
ly. In a note sent back with their man- 
uscript, an editor scoffed at the work, 
writing that "everyone knew" neurons 
dorit express MHC class I molecules. 

"The editor suggested we must have 
made a major mistake," Shatz recalls. 
"Now, at that point we could have said, 
'Okay, we made a mistake,' and just 
moved on. But it was a very robust result, 
and because I'd had other surprises from 
the brain, I reahzed that we should pay 
attention to this." 

"It turns out we'd run smack into a 
real dogma of biology," Shatz says with a 
srrdle. At that time, everyone believed 
that the brain operated in isolation from 
the immune system, a state called 
immune privilege. Shatz believes that 
other researchers had also run into the 
MHC protein in the brain but had set 
their observations aside in deference to 
the prevailing view. The more experi- 
ments Shatz and her colleagues conduct- 
ed, though, the more evidence emerged 
that MHC proteins were not only pre- 
sent in the brain but were also critical 
to brain wiring in fetal and early hfe. 

Once again, Shatz's work held imph- 
cations far beyond the visual system. In 



adults, the ability to rearrange neuronal 
connections is necessary for learning and 
making new memories, and she found 
that mice genetically engineered to lack 
MHC proteins displayed a profound 
defect in their ability to rewire in 
response to new experiences. 

"We realized these molecules aren't 
just in the visual regions of the brain, and 
that they are important not only in fetal 
hfe, but also through adulthood," Shatz 
says. "That was a critical step forward. 
At that point, several other researchers 
approached me and confessed, 'Well, I 
didn't beheve it until you showed it.' " 

In the immune system, MHC mole- 
cules help cells recognize each other by 
linking with partner molecules called 
receptors found on cell surfaces. 
Together, MHC and its partner receptor 
act like a lock and a key to bring cells 
together for communication. The 
researchers thought that MHC might 
act in the same way in the brain, by 
helping to bring nerve cells together at 
their synapses — the special connec- 
tions between two nerve cells. After a 
five-year search, Shatz recently found 
a partner for MHC in the brain. 

The work has generated a great deal of 
excitement, Shatz says, and already scien- 
tists are telling her informally that 
they've linked the MHC protein and its 
partner to diseases. "I think we're looking 
at the tip of the iceberg. This may prove to 
be our biggest advance in the lab." 

Everybody Freeze 

As important as synaptic changes are for 
development and learning, at some point 
the rewiring has to stop — too much 
synaptic flexibihty can be just as bad as 
too little. Most of the molecules identi- 
fied in the past 20 years have been posi- 
tive regulators of this remodeling. The 
experiment that Shatz and coworkers 
conducted with MHC's receptor showed 



that these molecules act in the opposite 
way — they put the brakes on synaptic 
plasticity rather than act as an accelerator. 

That observation has therapeutic value, 
Shatz says. "If you could block the signal- 
ing between MHC and its partner recep- 
tor in adults after stroke or brain damage, 
you might be able to regain the incredible 
plasticity that's present in fetal life and 
childhood. That may let you develop a 
pill to block this pathway and enhance 
memory — maybe something that would 
even help in Alzheimer's disease. Or per- 
haps it would allow you to re-create cir- 
cuits or to get one circuit to take over 
the functions of a damaged one." 

This latest insight brings Shatz full 
circle to her high school days and the 
reason she decided to pursue neurobi- 
ology research in the first place. At that 
time, her grandmother, a vibrant, active 
woman, suffered a debilitating stroke, 
and Shatz was frustrated that doctors 
could do nothing to help. 

Later, when Shatz decided to attend 
graduate school, two uncles, both neu- 
rologists, called her to tell her she was 
making a big mistake; she should be 
heading to medical school instead. Rec- 
ognizing that neurologists at the time 
had terrific diagnostic tools but few 
treatments to offer, she told them, "I'm 
going to go into the lab and get to work 
and see if maybe one day I can help 
people by making discoveries." 

But even having said that, Shatz 
admits that the link between her work 
and a possible treatment for brain injury 
is the most unexpected result she's had 
so far. "To think that, after all those years 
ago, when I told my uncles I was going to 
do research, I would be sitting here say- 
ing, 'Look, I've found a protein in the 
brain that might lead to drugs for 
stroke' — that's just amazing." ■ 

Pat McCaffrey is a freelance writer based in 
Auburndak, Massachusetts. 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



NAME: KILMER MCCULLY 
NEW TENET OFFERED: 

Homocysteine ploys a 
significant role in heart 
disease and stroke. 
SPARK OF INSPIRATION: 

The pathologies of two cases 
separated by decades — a 
nine-year-old girl and her 
eight-year-old uncle — combined 
with that of a two-month-old 
infant to implicate homocysteine 
in arteriosclerosis. 




Collateral 



Kilmer McCully 
connects the 
dots in cases 
separated 
by decades. 




dama 



hy Ann Marie Menting 




THIRTY-YEAR OLD 



protocol, six pathology slides, and one small, misshapen 
lump of tissue-studded paraffin were treasures to 
Kilmer McCully '59 when he scavenged them from 
pathology jetsam that had been stored in the attic 
above the old Massachusetts General Hospital morgue. 



It was 1968 and McCully, fresh from a 
residency in pathology, was on a mis- 
sion to review information on a case 
he had heard described during morn- 
ing rounds. 

Those rounds, led by the newly 
appointed chief of human genetics, John 
Littlefield '47, had touched on the case of 
a nine-year-old girl who had been seen 
at the hospital. The young gtrl's symp- 
toms included flushed cheeks, dislocat- 
ed lenses, and mild mental retardation. 
The diagnosis was homocystinuria, a 
metabolic disorder caused by the defec- 
tive activity of an enzyme. 



The diagnosis alone was enough to 
tweak the young pathologist's attention. 
Homocystinuria had been characterized 
just four years earlier. But what really 
registered on McCully's mental radar was 
a statement by the pediatrician in charge 
of the case: In 1933, the child's uncle had 
been diagnosed with similar symptoms 
and, at age eight, had died of stroke. 

Curious as to whether a link existed 
between the metabolic disorder and 
the death-dealing stroke, McCully had 
begun his hunt through the crammed 
glass, wax, and paper archives of the hos- 
pital's pathology department. With his 



finds in hand, he studied the protocol, 
re-embedded the tissue, prepared new 
shdes, and reviewed the pathology of 
the young stroke victim. And, just as the 
pathology report stated, the child had 
had arteriosclerosis of the carotid arter- 
ies with thrombosis and stroke. How 
interesting, thought McCully. 

Four months later, however, when a 
genetics rounds report included informa- 
tion on a two-month-old baby boy who 
had died of pneumonia and brain dam- 
age, interesting became fascinating; This 
child, who had been admitted because of 
failure to thrive, had been diagnosed with 
cobalamin C disease, a form of homo- 
cystinuria caused by a defect of the 
enzyme methionine synthase. When the 
amino acid methionine, produced during 
protein metabolism, breaks down in the 
body, homocysteine is produced. If 
methionine's metabolism is disrupted, as 
in cobalamin C disease, the levels of 
homocysteine build up in the plasma. 

The homocysteine disorder that had 
afflicted the nine-year-old girl, and — by 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



that have previously escapee . 
iBK notice are intellectual currency. What he was to learn v^as 
that intuiting and measuring such links could also cripple a career. 



genetic extension — the eight-year-old 
stroke victim, resulted from a mistake 
in the enzyme cystathionine P-synthase. 
McCully reasoned that if the infant's 
pathology also showed arterial plaques, 
high homocysteine levels would be the 
comjuon attribute of, and perhaps the 
unknown culprit in, the vascular damage 
that contributed to their deaths. 

McCully headed for the hospital's 
pathology department. He re-examined the 
infant's tissues and found clear evidence of 
rapidly progressing arteriosclerosis. 

For McCully, as for other physicians 
and researchers, exploring associations 
that have previously escaped notice are 
professional and intellectual currency, 
clues that can save lives or change sci- 
entific tenets. What McCully was to 
learn was that intuiting such links — 
and having the curiosity to measure 
their validity empirically — could also 
cripple a career. 

Strings Too Short to Use 

The implications of the children's 
pathologies grabbed McCully wholesale. 
Before finishing his pathology fellowship 
at the hospital, McCully had spent years 
in research, including a stint studying 
cholesterol in the laboratory of Konrad 
Bloch, the biochemist who won a Nobel 
Prize for his work on the biosynthesis 
of that steroid. Yet McCully had never 
heard of an association between the 
amino acid homocysteine and stroke or 
heart disease. 

"I've always been interested in new 
ideas and how they fit together," says 
McCully. "What I do is locate the differ- 
ent threads and try to find their pattern." 

Memories of classes at HMS surfaced, 
and he scoured his freshman-year notes 
for jottings from a nutrition lecture in 
which Fredrick Stare had discussed stud- 
ies showing that methonine supplements 
reduced cholesterol levels and arterial 



deposits in monkeys fed high- cholesterol 
diets. Vague recollections of a cormection 
between vitamin Eg and homocysteine 
had McCully knocking on the door of 
genetics chief Littlefield. Their conversa- 
tions spurred him to look through other 
medical school notes, this time for refer- 
ences to studies Unking vitamin Bg defi- 
ciency with arteriosclerosis in monkeys. 
These concepts started to weave together 
in McCuUy's head; he began to write the 
first paper on what would become his 
homocysteine theory of arteriosclerosis. 

"I had trouble sleeping," McCully 
recalls. "My wife told me I was spouting 
chemical formulas in the middle of the 
night. It was an intense period." 

McCully proceeded methodically, 
remaining true to his years of research 
training in the laboratories of such nota- 
bles as Paul Zamecnik '36, James Wat- 
son, and, of course, Bloch. 

McCully was a solitary worker but 
took soundings of his findings periodical- 
ly by discussing them with colleagues. 
With the help of Benjamin Castleman, 
the chief of the hospital's pathology 
department, McCully obtained sHdes of 
authenticated cases of homocystinuria 
from laboratories at Johns Hopkins and 
in Northern Ireland and compared them 
with his shdes. The pathologies matched. 
He submitted the tissues of the two- 
month-old boy to an electron micro- 
scopist for his interpretation of the 
pathology: His reading jibed with 
McCuUy's. And more biochemistry chats 
with Littlefield helped soUcUfy McCuUy's 
translation of just what homocysteine 
could be doing at the molecular level. 
Through these contacts, McCuUy checked 
and validated his findings. 

Publish and Perish 



One early spring day in 1969, McCully 
left the hospital and headed for the near- 
est post office. He gripped an envelope 



containing his manuscript describing the 
vascular pathology of homocysteinemia 
and its impUcations for arteriosclerosis. 
"I didn't want it to get lost in the house 
maU," he says. "So I walked it over." Three 
weeks later an editor at the American Jour- 
nal of Pathology contacted him. His manu- 
script had been accepted without change 
and was to be pubUshed immediately. In 
the ensuing months, McCuUy was flood- 
ed with reprint requests. 

"Scientists all over the world under- 
stood what I was saying and thought 
this concept was new and important." 
McCuUy pauses and his voice lowers as he 
remembers the significance those respons- 
es held for him as a young scientist. "I was 
astonished. It was extremely gratifying." 

The paper's publication began a furi- 
ous stretch of research for McCuUy. He set 
up shop in a first-floor laboratory in the 
hospital. There he studied ceU cultures of 
children with homocystinuria, discovered 
a sulfate metabolism pathway for homo- 
cysteine, and induced homocysteinemia 
in rabbits, producing vascular lesions that 
matched those in children with disorders 
of homocysteine metaboUsm and those 
found in adults with arteriosclerosis. 

His research excited him, his results 
fascinated him, and his pubUcations laid 
out the evidence for his theory of homo- 
cysteine's role as an arterial terrorist, 
damaging vessel waUs, triggering plaque 
formation, and ultimately causing arte- 
riosclerosis. He refined his theory, realiz- 
ing that although genetic, hormonal, and 
toxic factors such as cigarette smoking 
contributed to high levels of homocys- 
teine, the single most important factor 
was the dietary imbalance between too 
much methionine from dietary protein 
and too low an intake of foUc acid and 
vitamins Bg and Bp — aU needed to break 
down excess homocysteine. 

His investigations even began to 
insert cholesterol into the equation — 
as a substance captured in the arterial 



42 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 




3*^ 



V .- 







^ 



r 



plaques formed in response to homocys- 
teine-instigated damage, a secondary 
complication rather than the cause of 
the vascular changes. Funding rolled in, 
with the National Institutes of Health, 
the American Heart Association, and 
the American Cancer Society among the 
biggest sponsors. 

McCuUy toiled at this level for seven 
years. Then everything turtled. In 1976, 
Castleman retired, and a new depart- 
ment head was appointed. From him, 
McCuUy learned that the climate had 
changed, that "the Harvard elders — he 
didrit specify who — -just weren't inter- 
ested in my research." 

That same year, McCully's laboratory 
was moved out of the hospital's patholo- 
gy department and for two years he was 
sidelined to a laboratory outside the 
department before being moved again, 
this time to a basement facility His key 
technicians, research fellows, and stu- 
dents, fearing what they read in the aca- 
demic tea leaves, began to depart. 
McCully needed to support his research 
with grants, but without the skilled 
assistants to help with that research, 
grant-gaining became impossible. 

"In good conscience, I couldn't ask 
funders to support me under those condi- 



tions. So on January 1, 1979, I left. But I 
wasn't prepared for what would happen." 

Divine Providence 



For 27 months, McCully was unem- 
ployed — and seemingly unemployable. 
"I'd have interviews, but the same pat- 
tern would occur. I'd get some interest 
from an institute or hospital, I'd go for 
the interview, then all of a sudden every- 
thing would stop. One of my friends told 
me I was being blacklisted. I didn't know 
what to do. I wasn't sure why this was 
happening — or who was responsible." 

A position became available at the Vet- 
erans Administration Hospital in Prov- 
idence, Rhode Island, and McCully was 
invited for an interview — but soon a too- 
familiar clull began to cool the process. 
McCuUy was afraid. He was approaching 
a critical juncture. He had not worked for 
two years and had not kept up with con- 
tinuing education requirements; his med- 
ical hcense was possibly in jeopardy. He 
needed this position. 

So McCully sought the advice of 
Wihiam Homans, a respected civil rights 
attorney. For three hours, McCuUy told 
his tale to Homans. The attorney asked 
him to wait while he made some caUs — 



Homans knew some members of Mass- 
achusetts General Hospital's Board of 
Trustees. A day later, the freeze seemed 
to break. McCully got the job, his license 
renewal was approved, and, in 1981, he 
began working in Providence. 

McCully spent 20 years there, time 
that provided him the opportunity to 
continue his work on homocysteine; 
expand his general theory to identify the 
amino acid's role in aging, cancer, and 
arteriosclerosis; and explain his theory in 
more than 60 papers and two mono- 
graphs, products of what remains for him 
a totemic process — empirical research. 

Reflecting on those tough two years, 
McCuUy is still not sure why he was given 
the cold shoulder by the research commu- 
nity, although he speculates that his 
research had more than a Utde to do with 
it. That was, after aU, the time when cho- 
lesterol was named as the most-wanted 
substance, the evildoer most in need of 
measure and control. Yet along came 
McCuUy, pubUshing papers showing that 
a high homocysteine level was the culprit 
behind arteriosclerosis and contending 
that homocysteine could be kept in check 
simply by changing the diet to include 
more fruits and vegetables, less protein, 
and vitamin B supplements. 

McCuUy remains philosophical, how- 
ever, realizing that what happened to him 
has happened to others who made discov- 
eries out of step with their times. Now, as 
chief of the pathology department at the 
Veterans Affairs Medical Center in West 
Roxbury, Massachusetts, McCuUy contin- 
ues his investigations. Other researchers 
are also pursuing studies in the area and 
finding links between high homocysteine 
levels and such debUitating conditions as 
cardiovascular disease and Alzheimer's 
disease, expanding a field that was once 
aknost exclusively McCuUy's. ■ 

Ann Mark Mcnting is associate editor of the 
Harvard Medical Alumni BuUetin. 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 43 




'mm 



Catherine Wilfert turns her gaze 
to the smallest victims of HIV. 

No child left 




behind 



hy Ann Marie Menting 



HE KIBERA COMMUNITY SELF-HELP 

Programme in Nairobi, Kenya, provides children 
affected by AIDS with a haven. There they can learn 
carpentry and shoemaking, receive counseling on sex 
and HIV, and just be kids. The center also gives v/omen 
widowed by AIDS or burdened with HIV shelter, care. 



and counsel. It was there, one day six 
years ago, that Catherine Wilfert '62 
listened as nearly 40 beaming children 
serenaded her with chorus after chorus 
of "Happy Birthday to You." 

"It was a truly unbelievable birth- 
day," says Wilfert. "To be among those 
children reminded me that as over- 
whelming as the AIDS epidemic is, 
there is hope. I feel the work I am now 
doing is the most important of my life." 



Many take the celebration of a birth- 
day for granted, but for the children at 
the Kibera community program, growing 
older can be an accomplishment. Some, 
in fact, may be able to commemorate the 
passage of birthdays only because of 
research that Wilfert helped to conduct. 

As scientific director of the Eliza- 
beth Glaser Pediatric AIDS Founda- 
tion, Wilfert spends a good deal of time 
visiting sites where the foundation's 



efforts to stop the transmission of HIV 
from mothers to infants are under way. 
This work, however, is just the latest 
leg of a decades-long career during 
which Wilfert has studied how best to 
protect the smallest victims of the 
HIV/AIDS epidemic. Because of the 
research she and others have pioneered, 
tens of thousands of children in Africa — 
and throughout the world — are alive 
and healthy, beneficiaries of antiretro- 
viral regimens devised not only to treat 
women infected with HIV, but also to 
protect their babies, born and about- 
to-be-born. 

A Looming Shadow 

When Wilfert arrived at Duke Univer- 
sity in 1969, she was fresh from Chil- 
dren's Hospital Boston, where she had 
worked as a pediatrics resident and as 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



. V V i^ ^ how well children tolerated AZT. 

And we didrit know its risks for pregnant women. Yet we desperately 
needed answers on how to prevent HIV infection in babies." 



an instructor and a fellow in the virolo- 
gy laboratory of John Enders. Her 
knowledge of how infectious microor- 
ganisms affect children made her a wel- 
come addition to Duke's pediatrics 
group. Eleven years later, Wilfert had 
earned full professorships in pediatrics 
and microbiology and had been 
appointed chief of the medical center's 
pediatric infectious diseases unit. 
Although she had continued her inves- 
tigations of such organisms as varicella, 
echovirus, and Rickettsia, she found her 
research — and interest — increasingly 
pulled in the direction of a newly dis- 
covered bully: HIV. 

The epidemiological evidence made 
HIV a compelling subject. In North 
Carolina, as in other southern states, an 
uptick in the use of cocaine and injec- 
tion drugs — and the risky behaviors 
often associated with their use — had 
migrated from metropolitan centers to 
rural communities. In the early 1980s, 
children constituted 2 percent of the 
recognized AIDS cases in the United 
States. By mid-decade, that percentage 
was rapidly changing, with annual pro- 
jections for new HIV infections in chil- 
dren being tallied in the tens of thou- 
sands. That the projected numbers 
echoed those among women of child- 
bearing age did not escape WHfert's 
notice — or research lens. 

By 1986, Wilfert had established her- 
self as a leader in a new specialty — 
pediatric HIV/AIDS. That same year, 
she created Duke's pediatric HIV/AIDS 
program, one of the first of its kind in 
the nation. 

From her studies of mothers and 
infants attending Duke's clinic and from 
the work of researchers in other clinics 
in the United States, Wilfert document- 
ed vertical transmission of HIV — the 
passage of the virus from mothers to 
infants during pregnancy, childbirth, or 
breastfeeding — as the chief cause of 



pediatric infection. To Wilfert, the dev- 
astation HIV was bringing to adults fore- 
told a pediatrics disaster as weU. 

The Young and the Defenseless 

AIDS manifests differently in children 
than it does in adults. Vertical trans- 
mission allows HIV an entree to an 
immune system that is just learning to 
cope with environmental insults. 
Without much opposition, the aggres- 
sive virus disables the new immune 
system and renders the infant vulnera- 
ble to bacterial infections, including 
bouts with meningitis and pneumonia. 
Some infants also repeatedly contract 
chickenpox and other usually once-in- 
a-lifetime childhood diseases. 

While adults infected with HIV — 
even those without access to antiretro- 
viral therapies — can often live several 
years before showing AIDS symptoms, 
babies infected during gestation or 
through breastfeeding usually display 
symptoms within the first year of life. 
The virus kills 35 percent of its young 
victims by age one, 50 percent by age 
two, and 60 percent by age three. 

From Wnfert's tracking of the patho- 
genesis and natural history of the \'irus 
among infants at Duke's clinic, she 
knew it was vital to find a treatment 
that could improve infants' chances of 
fighting the virus or block it from them 
in the first place. 

A recently resurrected compound 
was about to fit Wilfert's bill. In 1985, 
researchers looking for drugs with anti- 
AIDS potential had dusted off a 20-year- 
old chemotherapeutic failure called azi- 
dothymidine (AZT). The scientists now 
found that AZT stalled HIV by increas- 
ing the number of immune cells in the 
body that fight the virus. Interestingly, 
AZT also proved to be an effective pro- 
phylaxis for adults who inadvertently 
exposed themselves to the virus through 



a needle stick or other contact with 
infected blood or fluids. 

Wilfert thought AZT might be a 
viable pediatric prevention tool. The 
drug, however, had been tested only in 
adults. "Testing drugs in children always 
lags behind adult testing," says Wilfert, 
"so we didn't know how well children 
tolerated AZT And we didrit know its 
risks for pregnant women. Yet we des- 
perately needed answers on how to pre- 
vent and treat HIV infection in babies." 

In 1989, she began researching the 
use of AZT for children infected with 
HIV and, when results showed promise, 
spread the word within the pediatric 
HIV/AIDS community. By 1994, the 
National Institute of Allergy and Infec- 
tious Diseases' Pediatric AIDS Clinical 
Trials Group, a group Wilfert chaired, 
conducted a large, multi-site study to 
test the safety and efficacy of AZT for 
HIV-infected pregnant women and 
their infants. The study, known as the 
Pediatric AIDS Clinical Trials Group 
protocol 076, or ACTG 076, produced 
groundbreaking results. 

Vertical transmission was reduced by 
two-thirds among HIV-infected preg- 
nant women who had taken AZT orally 
during the second or third trimester 
and intravenously during labor and 
delivery and whose babies had received 
AZT for the first six weeks after birth. 
Health providers finally had a means of 
preventing mother-to-child transmis- 
sion of HIV 

Implementing the AZT protocol in the 
United States reduced infant infections 
from the virus more than 80 percent. 
The country's rates for vertical trans- 
mission plummeted from 25 percent to 
2 percent; in 1999 North Carolina had 
only four reported cases of HIV trans- 
mission from mother to child. Wilfert 
had the tool she sought. 

Yet as Wilfert looked at internation- 
al transmission rates, she realized the 



46 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 




problem was far from solved. An 
opportunity to help stem the global 
rates of transmission presented itself 
in 1996 when she was recruited as the 
scientific director for the Pediatric 
AIDS Foundation. 

"I was excited to take the job," says 
WHfert, "because I would now be able 
to focus on international programs to 
prevent vertical transmission while 
being part of an organization with a 
long record of sponsoring research for 
HIV-infected children." 



Baby Steps 

Working in a nonprofit organization 
that funds programs in approximately 
1,100 clinics in 18 countries means Wil- 
fert's passport gets a workout. 
Although she has swapped the labora- 
tory for the field, her contributions to 
research on effective ways to prevent 
mother- to -child transmission of HIV 
have not abated. 

In Cameroon, South Africa, and other 
countries in sub-Saharan Africa, the 



foundation has been further evaluating 
antiretroviral regimens — including those 
involving the drug nevirapine — that 
offer women and babies prevention 
against HIV transmission. Although 
AZT remains a force in transmission 
prevention — and, together with nevi- 
rapine, is recommended for three 
months before childbirth — the delivery 
of this intervention presents problems 
for the health systems of many resource- 
scarce countries. Nevirapine, when 
administered in a single antepartum 
dose to the mother and a single dose to 
the newborn, has been shown to reduce 
vertical transmission 41 percent in 
breastfed babies for up to 18 months. 

Worldwide, an estimated 530,000 chil- 
dren are infected with HIV each year — 
that's nearly one child each minute. With 
90 percent of these infections linked to 
mother-to-child transmission, the stakes 
are high. Yet WHfert continues to find 
promise in the incremental progress that 
characterizes the fight to halt vertical 
transmission of HIV. Noting that the 
pool of need remains great despite the 
foundation's outreach to more than two 
million pregnant woman in the program's 
half-dozen years, WUfert admits, "That's a 
small number when you consider the 130 
nuUion babies born each year throughout 
the world — 30 million in Africa alone. 
But it shows what can be done within 
the existing infrastructures of resource- 
scarce countries. These steps are incred- 
ibly important in our international effort 
to prevent mother-to-child transmission." 

Wilfert's enthusiasm for her work is 
evident in her voice — strong and clear 
and laced with pragmatic optimism. 
With such hope, and continued 
research, her care-filled efforts may 
indeed help trump the deadly success of 
her viral opponent. ■ 

Ann Mark Ucnting is associate editor of the 
Harvard Medical Alumni Bulletin. 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



by Ray Babineau 



IT WAS A GLORIOUSLY SUNNY JULY DAY. 
I was in my sixty-thixd year, excited about moving 
into new office space, when I received a call from my 
internist. My recent PSA test, he told me, had shown 
a notable increase since the previous year. The 
absolute number was still low and hkely insignifi- 
cant, but he wanted to refer me to a urologist, just to be sure. 
The remaining weeks of summer passed with consulta- 
tions, antibiotics, repeat PSAs, and finally needle biopsies 
of my prostate. The biopsies were painless; the sharp jolt 
came several days later, on an equally sunny September day, 
when the urologist called. A community hospital had 
judged the biopsy slides to be suspicious but not definitive 
for cancer. The slides were being sent to the university-hos- 
pital pathologists for a second opinion. The sunshine of 
those two portentous days was a backhanded slap at my 
belief that I could detect auspicious patterns in nature. 

I felt in perfect health, and my exercise and diet regimens 
were too rigorous to allow cancer. The names on the slides 
must have been switched, I thought, or perhaps a poor 
staining preparation had caused this questionable reading. 
Suddenly peevish, I wondered why the urologist, who was 
university affiliated, had used a community hospital for 
precious me? I held on to the thought that I simply could not 
have cancer, but as two weeks passed my conviction of 
health eroded. During repeated flights to the Internet I 
began gathering enough information about prostate cancer 
to fill several large three -ring binders. Soon I felt prepared 
to give a crash course in Prostate Cancer 101, and I under- 
stood well Samuel Johnson's aphorism: "When a man 
knows he is to be hanged in a fortnight, it concentrates his 
mind wonderfully." 

On a follow-up visit the urologist told me that the biop- 
sies did indeed show malignancy. I could consider a radical 
prostatectomy or radioactive seed implantation. The urolo- 
gist favored the surgery, and he boasted of his ability to per- 
form this complicated procedure in 90 minutes. He hur- 
riedly disclosed the many possible complications and — I'm 
just sure — broke eye contact when he mentioned the risks 
of impotence and urinary incontinence as if they held equal 
weight with unevenness of closure at the wound. I knew all 
too well that those dreaded side effects of the conventional 
form of surgery he offered were frequent and could be pow- 
erfully life changing. 

I seethed with a silent rage toward him, a rage I'd had diffi- 
culty directing at impersonal fate. I had read enough in the 




48 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



^. ^^ 



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A PHYSICIAN TRAVELS 
TO A MEDICAL MECCA 
IN SEARCH OF A SENSE 
OF CONTROL OVER 
THE OUTCOME OF HIS 
OWN CANCER SURGERY 



The Cleveland Clinic is one of the nation's ni.edical meccas, set up 
tor those who believe they.iriust travel to iind the medical care 
they, seek. The trend is nothiug new; human bemgs have alwa^ 
1 lourneys to an Aesclepion,-a Benares^ OMXour.de§.as a hoi^ 
, and these modern Secular sites tuliill a similar nee 



neetie 
center 



intervening two months to know that 
several of his statements were wrong or 
misleadingly oversimphfied, and I felt 
contemptuous of his need to sell his 
own surgical services. When I asked 
about a specialized form of surgery that 
had a better chance of preserving poten- 
cy, to my dismay he waved it off as 
experimental. My plan was then clear: 
flee that office vvdth my x-rays and biop- 
sy report in hand. I told him I needed 
time and might seek a second opinion. 
The atmosphere turned frosty. No sale. 

The Wicket Gate 



From my frantic Internet searches I had 
learned that the type of surgery I want- 
ed — a nerve-sparing radical prostatec- 
tomy — had become well established 
since its development in the early 
1980s. The procedure was now avail- 
able in eight major medical centers in 
the United States, and I quickly settled 
on the Cleveland Clinic, both for its 
relative proximity to our home and 
because the name of one of its urologi- 
cal surgeons, Eric Klein, kept recurring 
in the literature. 

Not only had Klein recently coau- 
thored a book on prostate cancer, but he 
had also written the chapter on refine- 
ments to this meticulous surgical tech- 
nique, which aims to preserve two pre- 
cious nerves that take the long pelvic 
journey from spine to penis. This proce- 
dure takes about three hours to per- 
form, not 90 minutes. I ordered the book 
sent overnight from the pubhsher, read 
Klein's chapter, and, given my unshak- 
able reverence for the printed word, 
became convinced that Klein was the 
man and Cleveland was the place. 

The Cleveland Clinic is one of the 
nation's medical meccas, set up for 
those who beheve they must travel to 
find the medical care they seek. The 
trend is nothing new; human beings 
have always needed journeys to an 
Aesclepion, a Benares, or a Lourdes as a 



hope center, and these modern secular 
sites fulfiU a similar need. 

Glossy brochures depicted the 
Cleveland Chnic as a large campus with 
an extensive scattering of buildings, 
each catering to a particular diagnostic 
or treatment function, and v^dth several 
hotels catering to out-of-town patients 
and their families. My medical insur- 
ance covered out-of-town treatment, 
and making arrangements for the 
surgery proved easy. I found myseff 
talking with Klein on the phone within 
days and, since I was convinced that 
surgery with him was the option for 
me — sale — I was scheduled for the 
operating table in four weeks. I felt 
rehef at closure around one detail in a 
tide of uncertainty. 

The Slough of Despond 

Although she hid it bravely, this was a 
difficult time for my wife, Charmaine, 
as weU. In our shared bed we turned on 
twin spits of worry. Sadly, I had to teU 
our two sons of my news and let them 
know they were at increased risk for 
prostate cancer. They promptly went 
out and got basehne PSAs to manage 
their own anxiety. I was seized with 
genetic guilt. 

Those were tormented weeks with 
my patients as well. As their psychia- 
trist, I believed I should offer disclo- 
sure and time to discuss their reac- 
tions to the news. I ended up hearing 
more than I ever wanted to hear, hour 
after stressful hour. They recounted 
anesthesia deaths, fatalities on the 
operating table, complications, and 
infections. And they wondered — ever 
so delicately — about the risks of 
impotence, mirroring and elaborating 
my own worries. 

The Cleveland Clinic recommended 
that I donate two units of blood in 
advance, which the local Red Cross 
would process and ship to the clinic 
for storage should I need autologous 



transfusions during surgery. It felt 
strange watching the blood flow from 
my body and knovving it would be 
encased in plastic, labeled, refrigerat- 
ed, and consigned to the tender mer- 
cies of Federal Express and countless 
technicians along the journey to 
Cleveland. If all went without error, in 
a month we might be reunited miles 
from home, and my estranged blood 
could, if needed, resume its life-giving 
functions within me. 

Klein's office had offered me a choice 
of dates, and the Friday workup day 
v/ith surgery on the foUowing Monday 
morning seemed best. I knew surgeons 
were usually at their best in the morn- 
ing and early in the week, and I was 
trying to exert shreds of control — that 
comforting illusion — wherever I could. 
But we all fatigue. I hoped my pre- 
surgery weekend would not be the one 
during which my surgeon and his wife 
decided to divorce or learned that their 
teenagers were seUing ihicit drugs. 

The Celestial City 

The weeks passed. Charmaine and I 
arrived in Cleveland early on a Friday. 
Since the clinic was tailored to out- 
of-town travelers, we spent tliK entire 
workup day moving obediently from 
station to station for preoperative 
evaluation. It reminded me of having 
been processed into the U.S. Army, but 
with far more efficiency and courtesy. 
At the end of the day, I met Eric Klein. 
No, I had no more questions, but I had 
brought my copy of the book he had 
coauthored and wondered whether he 
would sign it for me. This was a first, 
he said, and, clearly tickled, auto- 
graphed it, wishing me a complete 
recovery. I had obtained the book and 
its author. Could I be in safer hands? 

As I was leaving his office, Klein 
joked that PSA would come to mean 
"Prostate-Specffic Anxiety." I smiled 
but did not tell him that that meaning 



50 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



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had held true for years. How many 
men escape that concern? 

Saturday and Sunday were unsched- 
uled, so Charmaine and I had time to 
kill. We wandered around downtown 
Cleveland on a cheerless winter day, 
the weather finally cooperating with 
my patterns'of-nature theory. I feigned 
interest in museums and art galleries. 
We ate excellent meals and drank 
intemperate amounts of wine of a qual- 
ity we had never dared buy before. We 
made love several times that weekend 
as if two or three decades of aging had 
been stripped away. Our passionate 
intensity was fueled by fears that Mon- 
day morning would bring dreadful 
possibilities: death on the operating 
table, news of inoperable cancer, or the 
surgical end to our ability to have 
intercourse. We absurdly tried once 
more on Sunday evening, failed miser- 
ably, laughed at ourselves, and col- 
lapsed into a troubled sleep. We had 
killed the weekend. 

At four in the morning, the requested 
wake-up call came. With difficulty, I had 



persuaded Charmaine that it would be 
pointless for her to rise at that hour. 
She would have plenty of agonizing 
time that morning in various waiting 
rooms. As compHant as a sacrificial vic- 
tim, I followed instructions for cleaning 
myself inside and out and descended to 
the hotel lobby. I checked at least twice 
with the desk clerk to make sure the 
shuttle bus was ruiming at that early 
hour. He reassured me with a calm well 
practiced through countless encoun- 
ters with fretful patients. 

StUl thinking magically, I felt cer- 
tain it was my peering into the dark- 
ness that made the bus finally materi- 
alize out of the fog. I climbed aboard, 
joining six other people. I had been 
the last to be picked up, and we were 
now being delivered to one treatment 
building after another: chemotherapy, 
radiation, different forms of surgery. 
It felt like an unusual mall, with the 
shuttle bus transporting us to shops 
not of our choosing. 

Finally, the only other remaining 
passengers were a couple who appeared 



to be in their early thirties. Their pres- 
ence seemed unfair — cancer too early 
in life. As they clung to each other, I 
couldn't tell which was the patient. 
Attempting clinical detachment, I 
wondered, was it she? Or was it he? 
They got off, both of them tearful and 
gripping hands with a desperation that 
suggested one of them might blow away 
that very day. 

As I watched them, my detachment 
suddenly crumbled. I realized I had 
been asking the wrong question. 
They were both the patient; cancer is a 
family diagnosis. As Charmaine and I 
had, they had made this frightening 
but still hopeful journey to a mecca 
of healing. ■ 

Ray Bahineau '63 is a clinical professor of 
psychiatry at the University of Rochester 
School of Medicine in Rochester, New York. 
After undergoing an operation free ofcompli' 
cations, he went on to have radiation treat- 
ment, an experience he recounted in the 
Winter 2003 issue of the Bulletin. He has 
been cancer free for five years. 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



51 




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HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



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Some patients are wilder than Others. I?)/ Stanley Perkins 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN I 53 




T HAD ALL THE ELEMENTS OF A HORROR FLICK: A GURNEY, TWO UNSUSPECTING 

doctors, a violent yet sedated patient. In dim light the gurney glides 
onto a freight elevator, a dull clang reverberating as the w^heels 
bump across the threshold. Slack- faced, with gazes riveted upward, 
the men watch the lighted arrow make its slow arc. Suddenly, a 
huge hairy hand springs up, seizing one of the men by the wrist. His 
eyes wide with panic, the doctor struggles to free himseh while the 
elevator lumbers on, slowly carrying the men and their charge out of 
sight. As every fan of horror knows, such a scene never bodes well for the 
doctor, n This time, though, the scene was real; I was the doctor and my 
patient was one ornery orangutan. In the two decades Tve volunteered at 
the San Diego Zoo and Wild Animal Park as a veterinary anesthesiologist, 
that tussle with Otis was the closest Tve come to being the guy who, 
when the elevator door opens, is sprawled lifeless on the floor. 



54 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 




THE NURTURE OF THE BEAST: Stanley Perkins administers 
anesthesia to an Asian elephant, far left, and to a baby 
bonobo, sometimes referred to as a pygmy chimpanzee, above. 



Otis was one of two male orangutans at the zoo. The 
other, Ken Allen, had earned acclaim as an escape artist. 
Whenever he grew bored, he would set about loosening the 
bolts of his cage. A quick shp through the door, a scamper up 
an incline, and a swing over a wall, and Ken Allen would be 
out, stroUing amid a crowd of people, as if he were just 
another zoo patron. Each time his keepers discovered one of 
his escape routes they closed it off, but he would devise a 
new one. He never seemed to mind being led back into his 
enclosure, though; he simply relished the challenge of find- 
ing new fhght paths. 

Otis had none of Ken Allen's geniality. He was a bundle of 
hirsute hostility, and he detested veterinarians — and anyone 
associated with them — most of all. With the highest 
strength'tO'Weight ratio of any primate, orangutans are not 
to be trifled with, especially when they have Otis's disposi- 
tion. Whenever I received a call from the zoo about an ani- 
mal in distress, I would jump into my car and head right 
over. If that call was about Otis, though, I had to fight the 
urge to jump into my car and head home instead. 

On the day he grabbed me, Otis was scheduled for 
cosmetic surgery: He needed a wart removed from his nose. 



But at the zoo even the simplest examinations require seda- 
tion. Jeff Zuba, the veterinary intern, tranquilized Otis with 
a dart so we could transport him to the veterinary hospital. 
I administered the anesthetic while the veterinarians 
removed the wart, conducted a physical exam, and untan- 
gled his long locks. 

During the return trip, I administered the last of the anes- 
thetic. Since we were only minutes from Otis's enclosure I 
figured we'd be fine. Unfortunately, I had forgotten the slug- 
gishness of the freight elevator that led down to his cage. 

Jeff and I were crammed into the tiny elevator with our 
bodies pressed against the gurney. I was holding the oxygen 
mask over Otis's face when suddenly I felt his prehensile 
grip. Now gasping for breath myself, I peeled his leathery 
digits one by one from my wrist and struggled to reinstate 
his oxygen mask. When the elevator door finally banged 
open, Jeff and I sprinted the gurney back to Otis's cage. By 
the time we had settled the orangutan in his bedroom, he 
was fully awake and spitting mad. Jeff later confessed the 
escape plan he had formulated as soon as Otis grabbed my 
wrist: He would dive under the gurney — and leave me to 
my own devices. 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 



55 



The Wild Bunch 

It was one of my human anesthesia patients who introduced 
me to the San Diego Zoo. During the preoperative visit, she 
mentioned her work as a zookeeper. I told her I had always 
loved animals, and she offered to take me on a behind-the- 
scenes tour of the zoo. After her recovery she made good on 
that offer and introduced me not only to her favorite animals, 
but also to one of the veterinarians. When I asked how anes- 
thetic practices differed for animals, he suggested I visit the 
zoo's hospital. 

On the appointed day I brought with me a new anesthetic 
we had begun using at my hospital. The veterinarians 
watched as I anesthetized one of the many stray chickens 
that stroll the zoo grounds. The experiment was a success: 
The chicken quickly dozed off, then just as quickly awak- 
ened after a predictable deep sleep. The chicken showed no 
sign of having been anesthetized. 

The veterinarians had all received training in anesthesia, 
but they now realized how much more advanced the field had 
become in human medicine. They began asking me to consult 
on their more unusual or difficult cases, or in cases involving 
rare or valuable animals. Each time I would bring specialized 
monitoring equipment to supplement the veterinarians' basic 
instrumentation. The veterinarians immediately adopted the 
anesthetic agents and techniques I showed them, and the Zoo- 
logical Society of San Diego raised money to provide them 
with advanced monitoring equipment. The zoo's patient mor- 
tality rate plummeted. 

Since that beginning, I've treated lions, tigers, and bears, 
as well as elephants, rhinos, zebras, and many other exotic 
species. Cheetahs are among my favorites. These beautiful 
fehnes are like oversized, sHghtly psychotic house cats. It's as if 
you had a hundred-pound Siamese cozying up to you, purring, 
hcking your hand — and dehvering an occasional swat. 

Each species — and each procedure — offers its own chal- 
lenges. Ungulates, for example, are exquisitely sensitive to 
such narcotics as morphine and fentanyl. The animals simply 
lose their stimulation to breathe. That vulnerabihty did, in 
fact, contribute to one loss; A giraffe's surgery proceeded 
smoothly, but later, when extubated, the animal simply 
stopped breathing. 

Giraffes pose difficulties for other reasons. When we 
administer anesthesia, the giraffe's elongated neck becomes 
floppy, so we have to strap it to a board or risk injuring verte- 
brae. The giraffe's long and narrow jaw makes it impossible to 
intubate using a laryngoscope, so we do the intubations bhnd, 
with an ear at one end of the tube monitoring the breath 
sounds as we advance the tube toward the larynx. 

Sleeping Giants 

The most technically complex animal I've anesthetized, 
though, is the elephant. The sheer weight of an anesthetized 



elephant lying on its side can cut blood flow to the muscles 
and compromise the animal's breathing, so we have to enrich 
the air supply with oxygen — and the surgeons have to be 
quick. But elephant breaths are like small windstorms. Hav- 
ing them depend on too small a ventilator tube would be hke 
asking a human to breathe through a straw all day long. 

To allow the elephant to breathe as naturally as possible 
while enriching the air with as much oxygen as we can, we 
constructed a rebreathing apparatus from an ordinary dryer 
exhaust hose, some large plastic bags, and a couple of oxy- 
gen tanks. Using this contraption, we inserted the ele- 
phant's trunk into the end of the dryer hose and performed 
what we believe was the first successful Caesarean section 
on an elephant. 

Raised in captivity, the elephant— Jean — likely did not real- 
ize she was pregnant. Since an elephant in labor can stop her 
contractions at vidU, we assume Jean, confused by the pains, 
stopped the labor and never restarted it. The fetus died in 
utero, and the decaying tissue was making Jean ill We 
performed a comphcated Caesarean to remove the fetus. 

My experience in anesthetizing elephants was put to eco- 
logical use more recently, when Jeff — my feUow Otis survivor 
and now a veterinarian at the Wild Animal Park — asked me 
to consult on an elephant population control project in south- 
ern Africa. Conservation efforts have been so effective in some 
of the region's national parks and land reserves that many 
have become overpopulated with elephants, threatening bio- 
diversity, habitat, and the success of other species. One park 
alone has 7,000 more elephants than the land can support. 

A team of veterinarians and conservationists has con- 
cluded that the most humane and effective approach for 
controlling the population is to reduce the birth rate by 
performing laparoscopic vasectomies on the older domi- 
nant males. We knew the anesthetic procedure had to be 
safe, reliable, and simple enough for the conservationists to 
do by themselves, with minimal equipment. Earlier this 
year, then, Jeff and I designed a portable breathing system. 
The resultant apparatus — a modification of the system we 
used for Jean — is an enormous endotracheal tube attached 
to an assemblage of large tubes, one-way valves, and oxygen 
ports. This system has since been used on multiple ele- 
phants in the field, without failure. 

The Wild Zoo Yonder 



As a research facility that works with so many exotic ani- 
mals, the medical center at the San Diego Wild Animal Park 
receives requests for assistance from all over the world. One 
day the call came from Anchorage; One of the elephants at 
the Alaska Zoo, Annabelle, needed a tooth extracted. The 
zoo had originally been built around Annabelle, when a local 
grocer won her in a national contest but had no place to 
house her. So when the veterinarian, veterinary dentist, and 
I all flew north to care for her, we became instant heroes. 



56 



HARVARD MEDICAL ALUMNI BULLETIN • AUTUMN 2006 



n 



V, 



The most memorable of 
the many trips I've since 
made to the Alaska Zoo, 
though, involved another 
dental problem. Binky, 
one of two polar bears 
there at the time, needed 
a root canal. He had been 
taken to the zoo as an 
orphaned cub found wan- 
dering the Alaskan Arctic, 
and now as an adult he 
was frustrated with his 
concrete-and'Steel home. 
In his efforts to chew to 
freedom he had broken 
three of his canine teeth. 

Binky was the first bear 
I had ever been asked 
to anesthetize, and I felt 
nervous. We tranquilized 
him, then dragged all 850 
pounds of bear from his 
bedroom to his exhibition 
area to ensure adequate 
workspace. I was using a 
lighted laryngoscope in 
my effort to insert a one- 
inch'Wide endotracheal 

tube. But the day was bright, his trachea was deep, and his 
tongue was flopping all around, so I couldn't see well enough 
to guide the tube. 

"Just reach in there," said Jim Oosterhuis, the head veteri- 
narian from San Diego, "and feel for his larynx." 

"You want me" — here I paused to stare at Jim — "to put my 
arm down the throat of a just shghtly sedated polar bear?" 

"Sure!" Jim said. "You'll have no problem at all." 

I had — until that moment, at least — trusted Jim implicit- 
ly. Drawing on that now shaky trust, I took a deep breath and 
plunged a hand down Binky's throat, pressing deeper until I 
could feel the tip of his epiglottis. With my other arm, I guid- 
ed the tube down his trachea. Just then I noticed that polar 
bear teeth — the sharpest of all ursine teeth — were resting 
inches below my shoulder. If that tranquilizer suddenly 
wears off, I thought, they're going to start calling me Lefty. 

But the maneuver worked, and Binky recovered well 
enough to gain international attention — even cult hero sta- 
tus — some years later for that very set of teeth. The catalyst 
was an Austrahan tourist who decided to scramble over two 
safety rails to get a good photo of him. Binky obligingly poked 
his head through the bars, but then wrapped his jaws around 
her leg. After a brief skirmish, he settled for her red-and-white 
sneaker. The tourist escaped with a broken leg, bite wounds, 
and a reputation for dimwittedness. 




INTO THE STRETCH: Stanley Perkins, top left, administers anesthesia to a giraffe. These animals, >vith 
their attenuated necks and long and narro>v jav^s, pose special challenges for anesthesiologists. 



Animal Magnetism 



L 



When I describe my work at the San Diego Zoo and Wild 
Animal Park, people ask why I didn't go into veterinary med- 
icine. I had considered doing so, but then realized I would 
find it emotionally draining to deal with suffering animals 
that couldn't understand what was happening to them. Now, 
by combining my vocation with my avocation, I'm able to 
enjoy the rewards of bringing the latest advances in human 
medicine to the veterinary world. 

My volunteer work with animals has given me perspective 
on my work with humans. Starting intravenous lines on 
people now seems easy after having started them on power- 
ful and struggling gorillas. Similarly, after intubating four- 
ton elephants, I no longer feel as anxious when morbidly 
obese patients come to my operating room. I also appreciate 
being able to explain to my patients what I'm doing — and to 
hear their thanks. 

And, best of all, sharing elevators with human patients on 
gurneys has always been blessedly uneventful. ■ 

Stanley Perkins W is an anesthesiologist at the Sharp Memorial Hospital 
in San Diego, where he cares for a variety of humans. When he's not 
puttingpeople — or animals — to sleep, he'sflyinghis Turho Commander 
with his dog. Amy, in the co-pilot's scat. 



AUTUMN 2006 • HARVARD MEDICAL ALUMNI BULLETIN 57 




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4t 



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3^ 

H* 

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